Template-fixed peptidomimetics with antimicrobial activity

ABSTRACT

Template-fixed β-hairpin peptidomimetics of the general formula 
     
       
         
         
             
             
         
       
     
     wherein Z is a template-fixed chain of 12 α-amino acid residues which, depending on their positions in the chain (counted starting from the N-terminal amino acid) are Gly, or Pro, or of certain types which, as the remaining symbols in the above formula, are defined in the description and the claims, and salts thereof, have the property to selectively inhibit the growth of or to kill microorganisms such as  Pseudomonas aeruginosa . They can be used as disinfectants for foodstuffs, cosmetics, medicaments or other nutrient-containing materials, or as medicaments to treat or prevent infections. 
     These β-hairpin peptidomimetics can be manufactured by processes which are based on a mixed solid- and solution phase synthetic strategy.

The present invention provides template-fixed β-hairpin peptidomimeticsincorporating a template-fixed chain of 12 α-amino acid residues which,depending on their positions in the chain, are Gly or Pro, or of certaintypes, as defined herein below. These template-fixed β-hairpin mimeticshave a selective antimicrobial activity. In addition, the presentinvention provides efficient synthetic processes by which thesecompounds can, if desired, be made in parallel library-format. Theseβ-hairpin peptidomimetics show improved efficacy, bioavailability,half-life and most importantly a significantly enhanced ratio betweenantibacterial activity on the one hand, and hemolysis of red blood cellson the other.

The growing problem of microbial resistance to established antibioticshas stimulated intense interest in developing novel antimicrobial agentswith new modes of action (H. Breithaupt, Nat. Biotechnol. 1999, 17,1165-1169). One emerging class of antibiotics is based on naturallyoccurring cationic peptides (T. Ganz, R. I. Lehrer, Mol. Medicine Today1999, 5, 292-297; R. M. Epand, H. J. Vogel, Biochim. Biophys. Acta 1999,1462, 11-28). These include disulfide-bridged β-hairpin and β-sheetpeptides (such as the protegrins [V. N. M.; 0. V. Shamova, H. A.Korneva, R. I. Lehrer, FEBS Lett. 1993, 327, 231-236], tachyplesins [T.Nakamura, H. Furunaka, T. Miyata, F. Tokunaga, T. Muta, S. Iwanaga, M.Niwa, T. Takao, Y. Shimonishi, Y. J. Biol. Chem. 1988, 263,16709-16713], and the defensins [R. I. Lehrer, A. K. Lichtenstein, T.Ganz, Annu. Rev. Immunol. 1993, 11, 105-128], amphipathic α-helicalpeptides (e.g. cecropins, dermaseptins, magainins, and mellitins [A.Tossi, L. Sandri, A. Giangaspero, Biopolymers 2000, 55, 4-30]), as wellas other linear and loop-structured peptides. Although the mechanisms ofaction of antimicrobial cationic peptides are not yet fully understood,their primary site of interaction is the microbial cell membrane (H. W.Huang, Biochemistry 2000, 39, 8347-8352). Upon exposure to these agents,the cell membrane undergoes permeabilization, which is followed by rapidcell death. However, more complex mechanisms of action, for example,involving receptor-mediated signaling, cannot presently be ruled out (M.Wu, E. Maier, R. Benz, R. E. Hancock, Biochemistry 1999, 38, 7235-7242).

The antimicrobial activities of many of these cationic peptides usuallycorrelate with their preferred secondary structures, observed either inaqueous solution or in membrane-like environments (N. Sitaram, R.Nagaraj, Biochim. Biophys. Acta 1999, 1462, 29-54). Structural studiesby nuclear magnetic resonance (NMR) spectroscopy have shown thatcationic peptides such as protegrin 1 (A. Aumelas, M. Mangoni, C.Roumestand, L. Chiche, E. Despaux, G. Grassy, B. Calas, A. Chavanieu, A.Eur. J. Biochem. 1996, 237, 575-583; R. L. Fahrner, T. Dieckmann, S. S.L. Harwig, R. I. Lehrer, D. Eisenberg, J. Feigon, J. Chem. Biol. 1996,3, 543-550) and tachyplesin I (K. Kawano, T. Yoneya, T. Miyata, K.Yoshikawa, F. Tokunaga, Y. Terada, S. J. Iwanaga, S. J. Biol. Chem.1990, 265, 15365-15367) adopt well defined β-hairpin conformations, dueto the constraining effect of two disulfide bridges. In protegrinanalogues lacking one or both of these disulfide bonds, the stability ofthe β-hairpin conformation is diminished, and the antimicrobial activityis reduced (J. Chen, T. J. Falla, H. J. Liu, M. A. Hurst, C. A. Fujii,D. A. Mosca, J. R. Embree D. J. Loury, P. A. Radel, C. C. Chang, L. Gu,J. C. Fiddes, Biopolymers 2000, 55, 88-98; S. L. Harwig, A. Waring, H.J. Yang, Y. Cho, L. Tan, R. I. Lehrer, R. J. Eur. J. Biochem. 1996, 240,352-357; M. E. Mangoni, A. Aumelas, P. Charnet, C. Roumestand, L.Chiche, E. Despaux, G. Grassy, B. Calas, A. Chavanieu, FEBS Lett. 1996,383, 93-98; H. Tamamura, T. Murakami, S. Noriuchi, K. Sugihara, A.Otaka, W. Takada, T. Ibuka, M. Waki, N. Tamamoto, N. Fujii, Chem. Pharm.Bull. 1995, 43, 853-858). Similar observations have been made inanalogues of tachyplesin I (H. Tamamura, R. Ikoma, M. Niwa, S.Funakoshi, T. Murakami, N. Fujii, Chem. Pharm. Bull. 1993, 41, 978-980)and in hairpin-loop mimetics of rabbit defensin NP-2 (S. Thennarasu, R.Nagaraj, Biochem. Biophys. Res. Comm. 1999, 254, 281-283). These resultsshow that the β-hairpin structure plays an important role in theantimicrobial activity and stability of these protegrin-like peptides.In the case of the cationic peptides preferring α-helical structures,the amphililic structure of the helix appears to play a key role indetermining antimicrobial activity (A. Tossi, L. Sandri, A. Giangaspero,A. Biopolymers 2000, 55, 4-30). Gramicidin S is a backbone-cyclicpeptide with a well defined β-hairpin structure (S. E. Hull, R.Karlsson, P. Main, M. M. Woolfson, E. J. Dodson, Nature 1978, 275,206-275) that displays potent antimicrobial activity againstgram-positive and gram-negative bacteria (L. H. Kondejewski, S. W.Farmer, D. S. Wishart, R. E. Hancock, R. S. Hodges, Int. J. PeptideProt. Res. 1996, 47, 460-466). The high hemolytic activity of gramicidinS has, however, hindered its widespread use as an antibiotic. Recentstructural studies by NMR have indicated that the high hemolyticactivity apparently correlates with the highly amphipathic nature ofthis cyclic β-hairpin-like molecule, but that it is possible todissociate antimicrobial and hemolytic activities by modulating theconformation and amphiphilicity (L. H. Kondejewski, M.Jelokhani-Niaraki, S. W. Farmer, B. Lix, M. Kay, B. D. Sykes, R. E.Hancock, R. S. Hodges, J. Biol. Chem. 1999, 274, 13181-13192; C.McInnesL. H. Kondejewski, R. S. Hodges, B. D. Sykes, J. Biol. Chem.2000, 275, 14287-14294).

A new cyclic antimicrobial peptide RTD-1 was reported recently fromprimate leukocytes (Y.-Q. Tang, J. Yuan, G. Ösapay, K. Ösapay, D. Tran,C. J. Miller, A. J. Oellette, M. E. Selsted, Science 1999, 286, 498-502.This peptide contains three disulfide bridges, which act to constrainthe cyclic peptide backbone into a hairpin geometry. Cleavage of thethree disulfide bonds leads to a significant loss of antimicrobialactivity. Analogues of protegrins (J. P. Tam, C. Wu, J.-L. Yang, Eur. J.Biochem. 2000, 267, 3289-3300) and tachyplesins (J.-P. Tam, Y.-A. Lu,J.-L. Yang, Biochemistry 2000, 39, 7159-7169; N. Sitaram, R. Nagaraij,Biochem. Biophys. Res. Comm. 2000, 267, 783-790) containing a cyclicpeptide backbone, as well as multiple disulfide bridges to enforce aamphiphilic hairpin structure, have also been reported. In these cases,removal of all the cystine constraints does not always lead to a largeloss of antimicrobial activity, but does modulate the membranolyticselectivity (J. P. Tam, C. Wu, J.-L. Yang, Eur. J. Biochem. 2000, 267,3289-3300).

A key issue in the design of new selective cationic antimicrobialpeptides are bioavailability, stability and reduced haemolytic activity.The naturally occurring protegrins and tachyplesins exert a significanthemolytic activity against human red blood cells. This is also the casefor protegrin analogues such as 1B367 (J. Chen, T. J. Falla, H. J. Liu,M. A. Hurst, C. A. Fujii, D. A. Mosca, J. R. Embree, D. J. Loury, P. A.Radel, C. C. Chang, L. Gu, J. C. Fiddes, Biopolymers 2000, 55, 88-98; C.Chang, L. Gu, J. Chen, U.S. Pat. No. 5,916,872, 1999). This highhemolytic activity essentially obviates its use in vivo, and representsa serious disadvantage in clinical applications. Also, the antibioticactivity of analogues often decreases significantly with increasing saltconcentration, such that under in vivo conditions (ca. 100-150 mM NaCl)the antimicrobial activity may be severely reduced.

Protegrin 1 exhibits potent and similar activity against gram-positiveand gram-negative bacteria as well as fungi in both low- and high-saltassays. This broad antimicrobial activity combined with a rapid mode ofaction, and their ability to kill bacteria resistant to other classes ofantibiotics, make them attractive targets for development of clinicallyuseful antibiotics. The activity against gram-positive bacteria istypically higher than against gram-negative bacteria. However, protegrin1 also exhibits a high hemolytic activity against human red blood cells,and hence a low selectivity towards microbial cells. Oriented CDexperiments (W. T. Heller, A. J. Waring, R. I. Lehrer, H. W. Huang,Biochemistry 1998, 37, 17331-17338) indicate that protegrin 1 may existin two different states as it interacts with membranes, and these statesare strongly influenced by lipid composition. Studies of cyclicprotegrin analogues (J.-P. Tam, C. Wu, J.-L. Yang, Eur. J. Biochem.2000, 267, 3289-3300) have revealed, that an increase in theconformational rigidity, resulting from backbone cyclization andmultiple disulfide bridges, may confer membranolytic selectivity thatdissociates antimicrobial activity from hemolytic activity, at least inthe series of compounds studied.

Protegrin 1 is an 18 residues linear peptide, with an amidated carboxylterminus and two disulfide bridges. Tachyplesin I contains 17 residues,also has an amidated carboxyl terminus and contains two disulfidebridges. Recently described backbone-cyclic protegrin and tachyplesinanalogues typically contain 18 residues and up to three disulfidebridges (J. P. Tam, C. Wu, J.-L. Yang, Eur. J. Biochem. 2000, 267,3289-3300; J. P. Tam, Y.-A. Lu, J.-L. Yang, Biochemistry 2000, 39,7159-7169; N. Sitaram, R. Nagaraij, Biochem. Biophys. Res. Comm. 2000,267, 783-790).

Cathelicidin, a 37-residue linear helical-type cationic peptide, andanalogues are currently under investigation as inhaled therapeuticagents for cystic fibrosis(CF) lung disease (L. Saiman, S. Tabibi, T. D.Starrier, P. San Gabriel, P. L. Winokur, H. P. Jia, P. B. McGray, Jr.,B. F. Tack, Antimicrob. Agents and Chemother. 2001, 45, 2838-2844; R. E.W. Hancock, R. Lehrer, Trends Biotechnol. 1998, 16, 82-88). Over 80% ofCF patients become chronically infected with pseudomonas aeruginosa (C.A. Demko, P. J. Biard, P. B. Davies, J. Clin. Epidemiol. 1995, 48,1041-1049; E. M. Kerem, R. Gold, H. Levinson, J. Pediatr. 1990, 116,714-719). Other antimicrobial peptides against Pseudomonads (Y. H. Yau,B. Ho, N. S. Tan, M. L. Ng, J. L. Ding, Antimicrob. Agents andChemother. 2001, 45, 2820-2825 and herein cited references), likeFALL-39, SMAP-29, and lepidopteran cecropin display a few of the desiredattributes like potent antimicrobial activity over a wide range of pH,rapid killing rate, and low hemolytic activity.

In the compounds described below, a new strategy is introduced tostabilize β-hairpin conformations in backbone-cyclic cationic peptidemimetics exhibiting selective antimicrobial activity. This involvestransplanting the cationic and hydrophobic hairpin sequence onto atemplate, whose function is to restrain the peptide loop backbone into ahairpin geometry.

Template-bound hairpin mimetic peptides have been described in theliterature (D, Obrecht, M. Altorfer, J. A. Robinson, Adv. Med. Chem.1999, 4, 1-68; J. A. Robinson, Syn. Lett. 2000, 4, 429-441) and theability to generate β-hairpin peptidomimetics using combinatorial andparallel synthesis methods has now been established (L. Jiang, K.Moehle, B. Dhanapal, D. Obrecht, J. A. Robinson, Helv. Chim. Acta. 2000,83, 3097-3112). Antibacterial template fixed peptidomimetics and methodsfor their synthesis have been described in International Patentapplications WO02/070547 A1 and WO2004/018503 A1 but these molecules donot exhibit high plasma stability selectivity and particularly highpotency.

The methods described herein allow the synthesis and screening of largehairpin mimetic libraries, which in turn considerably facilitatesstructure-activity studies, and hence the discovery of new moleculeswith potent selective antimicrobial and very low hemolytic activity tohuman red blood cells. The present strategy allows to synthesizeβ-hairpin peptidomimetics with novel selectivities towards variousmulti-drug resistant pseudomonas-strains.

The β-hairpin peptidomimetics of the present invention are compounds ofthe general formula

wherein

is a group of one of the formulae

wherein

is the residue of an L-α-amino acid with B being a residue of formula—NR²⁰CH(R⁷¹)— or the enantiomer of one of the groups A1 to A69 asdefined hereinafter;

is a group of one of the formulae

-   R¹ is H; lower alkyl; or aryl-lower alkyl;-   R² is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R³ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁴ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(p) (CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁵ is alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁶ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁷ is alkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(q)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁵;    —(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(r)(CHR⁶¹)_(s)COOR⁵⁷;    —(CH₂)_(r)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(r)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;    —(CH₂)_(r)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(r)(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁸ is H; Cl; F; CF₃; NO₂; lower alkyl; lower alkenyl; aryl;    aryl-lower alkyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)COR⁶⁴;-   R⁹ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R¹⁰ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R¹¹ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;    —(CH₂)_(m)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;    —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R¹² is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(r)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(r)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(r)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(r)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(r)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(r)(CHR⁶¹)_(s)C₆H₄R⁸;-   R¹³ is alkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(q)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(q)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(q)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(q)(CHR⁶¹)_(s)C₆H₄R⁸;-   R¹⁴ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷;    —(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶)₂;    —(CH₂)_(q)(CHR⁶¹)_(s)SOR⁶²; or —(CH₂)_(q)(CHR⁶¹)_(s)C₆H₄R⁸;-   R¹⁵ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R¹⁶ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)    NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;    —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;    —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R¹⁷ is alkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(q)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(q)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(q)—(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶)₂; —(CH₂)_(q)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(q)(CHR⁶¹)_(s)C₆H₄R⁸;-   R¹⁸ is alkyl; alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(q)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R¹⁹ is lower alkyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(p)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; or-   R¹⁸ and R¹⁹ taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;    —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;-   R²⁰ is H; alkyl; alkenyl; or aryl-lower alkyl;-   R²¹ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R²² is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R²³ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R²⁴ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R²⁵ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R²⁶ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; or-   R²⁵ and R²⁶ taken together can form: —(CH₂)₂₋₆—;    —(CH₂)_(r)O(CH₂)_(r); —(CH₂)_(r)S(CH₂)_(r)—; or    —(CH₂)_(r)NR⁵⁷(CH₂)_(r)—;-   R²⁷ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R²⁸ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)—OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s) COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R²⁹ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁶CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R³⁰ is H; alkyl; alkenyl; or aryl-lower alkyl;-   R³¹ is H; alkyl; alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;    —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁶CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;    —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;    —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R³² is H; lower alkyl; or aryl-lower alkyl;-   R³³ is H; alkyl, alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴R⁶³; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²;    —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁶CONR⁷⁸R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COR⁶⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)—CONR⁵⁸R⁵⁹, —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;    —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R³⁴ is H; lower alkyl; aryl, or aryl-lower alkyl;-   R³³ and R³⁴ taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;    —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;-   R³⁵ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;    —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;    —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸;-   R³⁶ is H, alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;    —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;    —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;    —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R³⁷ is H; F; Br; Cl; NO₂; CF₃; lower alkyl;    —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁶CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R³⁸ is H; F; Br; Cl; NO₂; CF₃; alkyl; alkenyl;    —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R³⁹ is H; alkyl; alkenyl; or aryl-lower alkyl;-   R⁴⁰ is H; alkyl; alkenyl; or aryl-lower alkyl;-   R⁴¹ is H; F; Br; Cl; NO₂; CF₃; alkyl; alkenyl;    —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁶CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁴² is H; F; Br; Cl; NO₂; CF₃; alkyl; alkenyl;    —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁴³ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;    —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;    —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁴⁴ is alkyl; alkenyl; —(CH₂)_(r)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(r)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(r)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(r)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(r)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(r)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(r)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(r)(CHR⁶¹)_(s)PO(OR⁶)₂; —(CH₂)_(r)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(r)(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁴⁵ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(s)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(s)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(s)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(s)(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁴⁶ is H; alkyl; alkenyl; or —(CH₂)_(o)(CHR⁶¹)_(p)C₆H₄R⁸;-   R⁴⁷ is H; alkyl; alkenyl; or —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;-   R⁴⁸ is H; lower alkyl; lower alkenyl; or aryl-lower alkyl;-   R⁴⁹ is H; alkyl; alkenyl; —(CHR⁶¹)_(s)COOR⁵⁷; (CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    (CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CHR⁶¹)_(s)SOR⁶²; or —(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁵⁰ is H; lower alkyl; or aryl-lower alkyl;-   R⁵¹ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(p)PO(OR⁶)₂; —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁵² is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(p)PO(OR⁶)₂; —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁵³ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(p)PO(OR⁶⁰)₂; —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁵⁴ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)COOR⁵⁷;    —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; or —(CH₂)_(o)(CHR⁶¹)_(s) C₆H₄R⁸;-   R⁵⁵ is H; lower alkyl; lower alkenyl; aryl-lower alkyl;    —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁷; —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴R⁶³;    —(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)—COR⁶⁴; —(CH₂)_(o)(CHR⁶¹)COOR⁵⁷; or    —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;-   R⁵⁶ is H; lower alkyl; lower alkenyl; aryl-lower alkyl;    —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁷; —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴R⁶³;    —(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)—COR⁶⁴; or —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;-   R⁵⁷ is H; lower alkyl; lower alkenyl; aryl lower alkyl; or    heteroaryl lower alkyl;-   R⁵⁸ is H; lower alkyl; lower alkenyl; aryl; heteroaryl; aryl-lower    alkyl; or heteroaryl-lower alkyl;-   R⁵⁹ is H; lower alkyl; lower alkenyl; aryl; heteroaryl; aryl-lower    alkyl; or heteroaryl-lower alkyl; or-   R⁵⁸ and R⁵⁹ taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;    —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;-   R⁶⁰ is H; lower alkyl; lower alkenyl; aryl; or aryl-lower alkyl;-   R⁶¹ is H, alkyl; alkenyl; aryl; heteroaryl; aryl-lower alkyl;    heteroaryl-lower alkyl; —(CH₂)_(p)OR⁵⁵; —(CH₂)_(p)NR³³R³⁴;    —(CH₂)_(p)OCONR⁷⁵R⁸²; —(CH₂)_(p)NR²⁰CONR⁷⁸R⁸²; —(CH₂)_(o)COOR⁵⁷; or    —(CH₂)_(o)PO(COR⁶)₂;-   R⁶² is lower alkyl; lower alkenyl; aryl, heteroaryl; or aryl-lower    alkyl;-   R⁶³ is H; lower alkyl; lower alkenyl; aryl, heteroaryl; aryl-lower    alkyl; heteroaryl-lower alkyl;    -   —COR⁶⁴; —COOR⁵⁷; —CONR⁵⁸R⁵⁹; —SO₂R⁶²; or —PO(OR⁶⁰)₂;-   R³⁴ and R⁶³ taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;    —(CH₂)₂S(CH₂)₂—; or    -   —(CH₂)₂NR⁵⁷(CH₂)₂—;-   R⁶⁴ is H; lower alkyl; lower alkenyl; aryl; heteroaryl; aryl-lower    alkyl; heteroaryl-lower alkyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁶⁵;    —(CH₂)_(p)(CHR⁶¹)_(s)SR⁶⁶; or —(CH₂)_(p)(CHR⁶¹)_(s)NR³⁴R⁶³;    —(CH₂)_(P)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²; —(CH₂)_(P)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²;-   R⁶⁵ is H; lower alkyl; lower alkenyl; aryl, aryl-lower alkyl;    heteroaryl-lower alkyl; —COR⁵⁷; —COOR⁵⁷; or —CONR⁵⁸R⁵⁹;-   R⁶⁶ is H; lower alkyl; lower alkenyl; aryl; aryl-lower alkyl;    heteroaryl-lower alkyl; or —CONR⁵⁸R⁵⁹;-   m is 2-4; o is 0-4; p is 1-4; q is 0-2; r is 1 or 2; s is 0 or 1;-   R⁶⁷ being H; Cl; Br; F; NO₂; —NR³⁴COR⁵⁷; lower alkyl; or lower    alkenyl;-   R⁶⁸ being H; Cl; Br; F; NO₂; —NR³⁴COR⁵⁷; lower alkyl; or lower    alkenyl;-   R⁶⁹ being H; Cl; Br; F; NO₂; —NR³⁴COR⁵⁷; lower alkyl; or lower    alkenyl; and-   R⁷⁰ being H; Cl; Br; F; NO₂; —NR³⁴COR⁵⁷; lower alkyl; or lower    alkenyl; with the proviso that at least two of R⁶⁷, R⁶⁸, R⁶⁹ and R⁷⁰    are H; and-   Z is a chain of 12 α-amino acid residues, the positions of said    amino acid residues in said chain being counted starting from the    N-terminal amino acid, whereby these amino acid residues are,    depending on their position in the chain, Gly or Pro, or of formula    -A-CO—, or of formula —B—CO—, or of one of the types-   C: —NR²⁰CH(R⁷²)CO—;-   D: —NR²⁰CH(R⁷³)CO—;-   E: —NR²⁰CH(R⁷⁴)CO—;-   F: —NR²⁰CH(R⁸⁴)CO—;-   H: —NR²⁰—CH(CO—)—(CH₂)₄₋₇—CH(CO—)—NR²⁰—;    —NR²⁰—CH(CO—)—(CH₂)_(p)SS(CH₂)_(p)—CH(CO—)—NR²⁰—;    —NR²⁰—CH(CO—)—(—(CH₂)_(p)NR²⁰CO(CH₂)_(p)—CH(CO—)—NR²⁰—; and    —NR²⁰—CH(CO—)—(—(CH₂)_(p)NR²⁰CONR²⁰(CH₂)_(p)—CH(CO—)—NR²⁰—;-   R⁷¹ is H; lower alkyl; lower alkenyl; —(CX₂)_(p)(CHR⁶¹)_(s)OR⁷⁵;    —(CX₂)_(p)(CHR⁶¹)_(s)SR⁷⁵; —(CX₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;    —(CX₂)_(p)(CXR⁶¹)_(s)OCONR³³R⁷⁵; —(CX₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CX₂)_(o)(CHR⁶¹)_(s)COOR⁷⁵; —(CX₂)_(p)CONR⁵⁸R⁵⁹;    —(CX₂)_(p)PO(OR⁶²)₂; —(CX₂)_(p)SO₂R⁶²; or    —(CX₂)_(o)—C₆R⁶⁷R⁶⁸R⁶⁹R⁷⁰R⁷⁶;-   R⁷² is H; lower alkyl; lower alkenyl; —(CX₂)_(p)(CHR⁸⁶)_(s)OR⁸⁵; or    —(CX₂)_(p)(CHR⁸⁶)_(s)SR⁸⁵;-   R⁷³ is —(CX₂)_(o)R⁷⁷; —(CX₂)_(r)O(CH₂)_(o)R⁷⁷;    —(CX₂)_(r)S(CH₂)_(o)R⁷⁷; or —(CX₂)_(r)NR²⁰(CH₂)_(o)R⁷⁷;-   R⁷⁴ is —(CX₂)_(p)NR⁷⁸R⁷⁹; —(CX₂)_(p)NR⁷⁷R⁸⁰;    —(CX₂)_(p)C(═NR⁸⁰)NR⁷⁸R⁷⁹; —(CX₂)_(p)C(═NOR⁵⁰)NR⁷⁸R⁷⁹;    —(CX₂)_(p)C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹; —(CX₂)_(p)NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;    —(CX₂)_(p)N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰; —(CX₂)_(p)C₆H₄NR⁷⁸R⁷⁹;    —(CX₂)_(p)C₆H₄NR⁷⁷R⁸⁰; —(CX₂)_(p)C₆H₄C(═NR⁸⁰)NR⁷⁸R⁷⁹;    —(CX₂)_(p)C₆H₄C(═NOR⁵⁰)NR⁷⁸R⁷⁹; —(CX₂)_(p)C₆H₄C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;    —(CX₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;    —(CX₂)_(p)C₆H₄N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰; —(CX₂)_(r)O(CX₂)_(m)NR⁷⁸R⁷⁹;    —(CX₂)_(r)O(CX₂)_(m)NR⁷⁷R⁸⁰; —(CX₂)_(r)O(CX₂)_(p)C(═NR⁸⁰)NR⁷⁸R⁷⁹;    —(CX₂)_(r)O(CX₂)_(p)C(═NOR⁵⁰)NR⁷⁸R⁷⁹;    —(CX₂)_(r)O(CX₂)_(p)C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;    —(CX₂)_(m)O(CH₂)_(m)NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;    —(CX₂)_(r)O(CX₂)_(m)N═C(NR⁷⁹R⁸⁰)NR⁷⁹R⁸⁰;    —(CX₂)_(r)O(CX₂)_(p)C₆H₄CNR⁷⁸R⁷⁹;    —(CX₂)_(r)O(CX₂)_(p)C₆H₄C(═NR⁸⁰)NR⁷⁸R⁷⁹;    —(CX₂)_(r)O(CX₂)_(p)C₆H₄C(═NOR⁵⁰)NR⁷⁸R⁷⁹;    —(CX₂)_(r)O(CX₂)_(p)C₆H₄C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;    —(CX₂)_(r)O(CX₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;    —(CX₂)_(r)S(CX₂)_(m)NR⁷⁸R⁷⁹; —(CX₂)_(r)S(CX₂)_(m)NR⁷⁷R⁸⁰;    —(CX₂)_(r)S(CX₂)_(p)C(═NR⁸⁰)NR⁷⁸R⁷⁹;    —(CX₂)_(r)S(CX₂)_(p)C(═NOR⁵⁰)NR⁷⁸R⁷⁹;    —(CX₂)_(r)S(CX₂)_(p)C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;    —(CX₂)_(r)S(CX₂)_(m)NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;    —(CX₂)_(r)S(CX₂)_(m)N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰;    —(CX₂)_(r)S(CX₂)_(p)C₆H₄CNR⁷⁸R⁷⁹;    —(CX₂)_(r)S(CX₂)_(p)C₆H₄C(═NR⁸⁰)NR⁷⁸R⁷⁹;    —(CX₂)_(r)S(CX₂)_(p)C₆H₄C(═NOR⁵⁰)NR⁷⁸R⁷⁹;    —(CX₂)_(r)S(CX₂)_(p)C₆H₄C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;    —(CX₂)_(r)S(CX₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹; —(CX₂)_(p)NR⁸⁰COR⁶⁴;    —(CX₂)_(p)NR⁸⁰COR⁷⁷; —(CX₂)_(p)NR⁸⁰CONR⁷⁸R⁷⁹;    —(CX₂)_(p)C₆H₄NR⁸⁰CONR⁷⁸R⁷⁹; or    —(CX₂)_(p)NR²⁰CO—[(CX₂)_(u)—XX]_(t)—CH₃ where XX is —O—; —NR²⁰—, or    —S—; u is 1-3, and t is 1-6;-   R⁷⁵ is lower alkyl; lower alkenyl; or aryl-lower alkyl;-   R³³ and R⁷⁵ taken together can form: —(CX₂)₂₋₆—; —(CX₂)₂O(CX₂)₂—;    —(CX₂)₂S(CX₂)₂—; or —(CX₂)₂NR⁵⁷(CX₂)₂—;-   R⁷⁵ and R⁸² taken together can form: —(CX₂)₂₋₆—; —(CX₂)₂O(CX₂)₂—;    —(CX₂)₂S(CX₂)₂—; or —(CX₂)₂NR⁵⁷(CX₂)₂—;-   R⁷⁶ is H; lower alkyl; lower alkenyl; aryl-lower alkyl;    —(CX₂)_(o)R⁷²; —(CX₂)_(o)SR⁷²; —(CX₂)_(o)NR³³R³⁴;    —(CX₂)_(o)CONR³³R⁷⁵; —(CX₂)_(o)NR²⁰CONR³³R⁸²; —(CX₂)_(o)COOR⁷⁵;    —(CX₂)_(o)CONR⁵⁸R⁵⁹; —(CX₂)_(o)PO(OR⁶⁰)₂; —(CX₂)_(p)SO₂R⁶²; or    —(CX₂)_(o)COR⁶⁴;-   R⁷⁷ is —C₆R⁶⁷R⁶⁸R⁶⁹R⁷⁰R⁷⁶; or a heteroaryl group of one of the    formulae

-   R⁷⁸ is H; lower alkyl; aryl; or aryl-lower alkyl;-   R⁷⁸ and R⁸² taken together can form: —(CX₂)₂₋₆—; —(CX₂)₂O(CX₂)₂—;    —(CX₂)₂S(CX₂)₂—; or —(CX₂)₂NR⁵⁷(CX₂)₂—;-   R⁷⁹ is H; lower alkyl; aryl; or aryl-lower alkyl; or-   R⁷⁸ and R⁷⁹, taken together, can be —(CX₂)₂₋₇—; —(CX₂)₂O(CX₂)₂—; or    —(CX₂)₂NR⁵⁷(CX₂)₂—;-   R⁸⁰ is H; or lower alkyl;-   R⁸¹ is H; lower alkyl; or aryl-lower alkyl;-   R⁸² is H; lower alkyl; aryl; heteroaryl; or aryl-lower alkyl;-   R³³ and R⁸² taken together can form: —(CX₂)₂₋₆—; —(CX₂)₂O(CX₂)₂—;    —(CX₂)₂S(CX₂)₂—; or —(CX₂)₂NR⁵⁷(CX₂)₂—;-   R⁸³ is H; lower alkyl; aryl; or —NR⁷⁸R⁷⁹;-   R⁸⁴ is —(CX₂)_(m)(CHR⁶¹)_(s)OH; —(CX₂)_(p)CONR⁷⁸R⁷⁹;    —(CX₂)_(p)NR⁸⁰CONR⁷⁸R⁷⁹; —(CX₂)_(p)C₆H₄CONR⁷⁸R⁷⁹; or    —(CX₂)_(p)C₆H₄NR⁸⁰CONR⁷⁸R⁷⁹;-   R⁸⁵ is lower alkyl; or lower alkenyl;-   R⁸⁶ is H, alkyl; alkenyl; —(CX₂)_(p)OR⁸⁵; —(CX₂)_(p)SR⁸⁵-   R⁸⁷ is H; alkyl; alkenyl; heteroaryl, aryl-lower alkyl;    —(CX₂)_(p)OR⁵⁵; —(CX₂)_(p)OCONR⁷⁵R⁸²; —(CX₂)_(p)NR²⁰CONR⁷⁸R⁸²;    —(CX₂)_(p)COOR⁵⁷, or —(CX₂)_(p)PO(OR⁶⁰)₂;-   X is H; or optionally halogen;-   with the proviso that in said chain of 12 α-amino acid residues Z    the amino acid residues in positions 1 to 12 are, in a preferred    embodiment:    -   P1: of type C or of type D or of type E or of type F, or the        residue is Pro;    -   P2: of type D or of type E;    -   P3: of type C or of type D, or the residue is Gly or Pro;    -   P4: of type C or of type E or of type F, or the residue is Gly        or Pro;    -   P5: of type E or of type D or of type C, or the residue is Gly        or Pro;    -   P6: of type E or of type F or of type C or of formula -A-CO—, or        the residue is Gly or Pro;    -   P7: of type C or of type E or of type F or of formula —B—CO—;    -   P8: of type D or of type C, or of Type F, or the residue is Pro;    -   P9: of type C or of type E or of type D or of type F;    -   P10: of type E;    -   P11: of type C or of type F, or the residue is Pro or Gly; and    -   P12: of type C or of type D or of type E or of type F, or the        residue is Pro; or    -   P4 and P9 and/or P2 and P11, taken together, can form a group of        type H; and    -   at P6, P10 and P11 also D-isomers being possible;        or, alternatively, but in a less preferred embodiment:    -   P1: of type C or of type D or of type E or of type F, or the        residue is Pro;    -   P2: of type C or of type F, or the residue is Pro or Gly;    -   P3: of type E;    -   P4: of type C or of type E or of type D or of type F;    -   P5: of type D or of type C, or of type F, or the residue is Pro;    -   P6: of type C or of type E or of type F or of formula —B—CO—;    -   P7: of type E or of type F or of type C or of formula -A-CO—, or        the residue is Gly or Pro;    -   P8: of type E or of type D or of type C, or the residue is Gly        or Pro;    -   P9: of type C or of type E or of type F; or the residue is Gly        or Pro;    -   P10: of type C or of type D, or the residue is Gly or Pro;    -   P11: of type D or of type E; and    -   P12: of type C or of type D or of type E or of type F, or the        residue is Pro; or    -   P4 and P9 and/or P2 and P11, taken together, can form a group of        type H; and    -   at P2, P3, and P7 also D-isomers being possible;        and pharmaceutically acceptable salts thereof.

In accordance with the present invention these β-hairpin peptidomimeticscan be prepared by a process which comprises

(a) coupling an appropriately functionalized solid support with anappropriately N-protected derivative of that amino acid which in thedesired end-product is in position 5, 6 or 7, any functional group whichmay be present in said N-protected amino acid derivative being likewiseappropriately protected;(b) removing the N-protecting group from the product thus obtained;(c) coupling the product thus obtained with an appropriately N-protectedderivative of that amino acid which in the desired end-product is oneposition nearer the N-terminal amino acid residue, any functional groupwhich may be present in said N-protected amino acid derivative beinglikewise appropriately protected;(d) removing the N-protecting group from the product thus obtained;(e) repeating steps (c) and (d) until the N-terminal amino acid residuehas been introduced;(f) coupling the product thus obtained with a compound of the generalformula

wherein

is as defined above and X is an N-protecting group or, if

is to be group (a1) or (a2), above, alternatively

-   -   (fa) coupling the product obtained in step (e) with an        appropriately N-protected derivative of an amino acid of the        general formula

HOOC—B—H  III

or

HOOC-A-H  IV

-   -   wherein B and A are as defined above, any functional group which        may be present in said N-protected amino acid derivative being        likewise appropriately protected;    -   (fb) removing the N-protecting group from the product thus        obtained; and    -   (fc) coupling the product thus obtained with an appropriately        N-protected derivative of an amino acid of the above general        formula IV and, respectively, III, any functional group which        may be present in said N-protected amino acid derivative being        likewise appropriately protected;        (g) removing the N-protecting group from the product obtained in        step (f) or (fc);        (h) coupling the product thus obtained with an appropriately        N-protected derivative of that amino acid which in the desired        end-product is in position 12, any functional group which may be        present in said N-protected amino acid derivative being likewise        appropriately protected;        (i) removing the N-protecting group from the product thus        obtained;        (j) coupling the product thus obtained with an appropriately        N-protected derivative of that amino acid which in the desired        end-product is one position farther away from position 12, any        functional group which may be present in said N-protected amino        acid derivative being likewise appropriately protected;        (k) removing the N-protecting group from the product thus        obtained;        (l) repeating steps (j) and (k) until all amino acid residues        have been introduced;        (m) if desired, selectively deprotecting one or several        protected functional group(s) present in the molecule and        appropriately substituting the reactive group(s) thus liberated;        (o) detaching the product thus obtained from the solid support;        (p) cyclizing the product cleaved from the solid support;        (q) if desired, forming one or two interstrand linkage(s)        between side-chains of appropriate amino acid residues at        opposite positions of the β-strand region;        (r) removing any protecting groups present on functional groups        of any members of the chain of amino acid residues and, if        desired, any protecting group(s) which may in addition be        present in the molecule; and        (s) if desired, converting the product thus obtained into a        pharmaceutically acceptable salt or converting a        pharmaceutically acceptable, or unacceptable, salt thus obtained        into the corresponding free compound of formula I or into a        different, pharmaceutically acceptable, salt.

Alternatively, the peptidomimetics of the present invention can beprepared by

(a′) coupling an appropriately functionalized solid support with acompound of the general formula

wherein

is as defined above and X is an N-protecting group or, if

is to be group (a1) or (a2), above, alternatively

-   -   (a′a) coupling said appropriately functionalized solid support        with an appropriately N-protected derivative of an amino acid of        the general formula

HOOC—B—H  III

or

HOOC-A-H  IV

-   -   wherein B and A are as defined above, any functional group which        may be present in said N-protected amino acid derivative being        likewise appropriately protected;    -   (a′b) removing the N-protecting group from the product thus        obtained; and    -   (a′c) coupling the product thus obtained with an appropriately        N-protected derivative of an amino acid of the above general        formula IV and, respectively, III, any functional group which        may be present in said N-protected amino acid derivative being        likewise appropriately protected;        (b′) removing the N-protecting group from the product obtained        in step (a′) or (a′c);        (c′) coupling the product thus obtained with an appropriately        N-protected derivative of that amino acid which in the desired        end-product is in position 12, any functional group which may be        present in said N-protected amino acid derivative being likewise        appropriately protected;        (d′) removing the N-protecting group from the product thus        obtained;        (e′) coupling the product thus obtained with an appropriately        N-protected derivative of that amino acid which in the desired        end-product is one position farther away from position 12, any        functional group which may be present in said N-protected amino        acid derivative being likewise appropriately protected;        (f) removing the N-protecting group from the product thus        obtained;        (g′) repeating steps (e′) and (f′) until all amino acid residues        have been introduced;        (h′) if desired, selectively deprotecting one or several        protected functional group(s) present in the molecule and        appropriately substituting the reactive group(s) thus liberated;        (i′) detaching the product thus obtained from the solid support;        (j′) cyclizing the product cleaved from the solid support;        (k′) if desired forming one or two interstrand linkage(s)        between side-chains of appropriate amino acid residues at        opposite positions of the β-strand region;        (l′) removing any protecting groups present on functional groups        of any members of the chain of amino acid residues and, if        desired, any protecting group(s) which may in addition be        present in the molecule; and        (m′) if desired, converting the product thus obtained into a        pharmaceutically acceptable salt or converting a        pharmaceutically acceptable, or unacceptable, salt thus obtained        into the corresponding free compound of formula I or into a        different, pharmaceutically acceptable, salt.

The peptidomimetics of the present invention can also be enantiomers ofthe compounds of formula I. These enantiomers can be prepared by amodification of the above processes in which enantiomers of all chiralstarting materials are used.

As used in this description, the term “alkyl”, taken alone or incombinations, designates saturated, straight-chain or branchedhydrocarbon radicals having up to 24, preferably up to 12, carbon atoms,optionally substituted with halogen. Similarly, the term “alkenyl”designates straight chain or branched hydrocarbon radicals having up to24, preferably up to 12, carbon atoms and containing at least one or,depending on the chain length, up to four olefinic double bonds,optionally substituted with halogen. The term “lower” designatesradicals and compounds having up to 6 carbon atoms. Thus, for example,the term “lower alkyl” designates saturated, straight-chain or branchedhydrocarbon radicals having up to 6 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, sec.-butyl, isobutyl, tert.-butyl and thelike. The term “aryl” designates aromatic carbocyclic hydrocarbonradicals containing one or two six-membered rings, such as phenyl ornaphthyl, which may be substituted by up to three substituents such asBr, Cl, F, CF₃, NO₂, lower alkyl or lower alkenyl. The term “heteroaryl”designates aromatic heterocyclic radicals containing one or two five-and/or six-membered rings, at least one of them containing up to threeheteroatoms selected from the group consisting of O, S and N and saidring(s) being optionally substituted; representative examples of suchoptionally substituted heteroaryl radicals are indicated hereinabove inconnection with the definition of R⁷⁷.

The structural element -A-CO— designates amino acid building blockswhich in combination with the structural element —B—CO— form templates(a1) and (a2). Templates (a) through (p) constitute building blockswhich have an N-terminus and a C-terminus oriented in space in such away that the distance between those two groups may lie between 4.0-5.5A. A peptide chain Z is linked to the C-terminus and the N-terminus ofthe templates (a) through (p) via the corresponding N- and C-termini sothat the template and the chain form a cyclic structure such as thatdepicted in formula I. In a case as here where the distance between theN- and C-termini of the template lies between 4.0-5.5 A the templatewill induce the H-bond network necessary for the formation of aβ-hairpin conformation in the peptide chain Z. Thus template and peptidechain form a β-hairpin mimetic.

The β-hairpin conformation is highly relevant for the anti-bacterialactivity of the β-hairpin mimetics of the present invention. Theβ-hairpin stabilizing conformational properties of the templates (a)through (p) play a key role not only for the selective antibacterialactivity but also for the synthetic processes defined hereinabove, asincorporation of the templates at the beginning or near the middle ofthe linear protected peptide precursors enhances cyclization yieldssignificantly.

Building blocks A1-A69 belong to a class of amino acids wherein theN-terminus is a secondary amine forming part of a ring. Among thegenetically encoded amino acids only proline falls into this class. Theconfiguration of building block A1 through A69 is (D), and they arecombined with a building block —B—CO— of (L)-configuration. Preferredcombinations for templates (a1) are -^(D)A1-CO—^(L)B—CO— to^(D)A69-CO—^(L)B—CO—. Thus, for example, ^(D)Pro-^(L)Pro constitutes theprototype of templates (a1). Less preferred, but possible arecombinations -^(L)A1-CO—^(D)B—CO— to ^(L)A69-CO—^(D)B—CO— formingtemplates (a2). Thus, for example, ^(L)Pro-^(D)Pro constitutes theprototype of template (a2).

It will be appreciated that building blocks -A1-CO— to -A69-CO— in whichA has (D)-configuration, are carrying a group R¹ at the α-position tothe N-terminus. The preferred values for R¹ are H and lower alkyl withthe most preferred values for R¹ being H and methyl. It will berecognized by those skilled in the art, that A1-A69 are shown in(D)-configuration which, for R¹ being H and methyl, corresponds to the(R)-configuration. Depending on the priority of other values for R¹according to the Calm, Ingold and Prelog-rules, this configuration mayalso have to be expressed as (S).

In addition to R¹ building blocks -A1-CO— to -A69-CO— can carry anadditional substituent designated as R² to R¹⁷. This additionalsubstituent can be H, and if it is other than H, it is preferably asmall to medium-sized aliphatic or aromatic group. Examples of preferredvalues for R² to R¹⁷ are:

-   -   R²: H; lower alkyl; lower alkenyl; (CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); (CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); (CH₂)_(m)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; R³³ and R³⁴        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; R⁵⁷: H; or lower alkyl); (CH₂)_(m)OCONR³³R⁷⁵        (where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower        alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(s)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³:H; or lower alkyl; or lower alkenyl; R⁸²:H; or lower alkyl;        or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl;        or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R³: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        (CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁴: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(s)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)R²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³:        H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or        R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl;        or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R⁵: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: lower        alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; R⁵⁷: where H; or lower alkyl);        (CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³:        H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or        R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); (CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: alkyl; alkenyl; aryl; and aryl-lower alkyl;        heteroaryl-lower alkyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower        alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower        alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and        R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R⁶: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R⁷: lower alkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵: lower        alkyl; or lower alkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(q)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(q)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        (CH₂)_(q)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³:        H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or        R³³ and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(q)N(R)²⁰COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(s)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(q)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl;        or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(r)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); (CH₂)_(r)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵        (where R⁵⁵: lower alkyl; or lower alkenyl); (CH₂)_(o)SR⁵⁶ (where        R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where        R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or        R³³ and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower        alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or        lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower        alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower        alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower        alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and        R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁹: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: lower        alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R¹⁰: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R¹¹: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R¹²: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(s)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: H; or        lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(r)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(r)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(r)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; CF₃; lower alkyl;        lower alkenyl; or lower alkoxy).    -   R¹³: lower alkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(q)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(q)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(q)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(q)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(r)COO⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(q)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(r)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(r)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R¹⁴: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R¹⁵: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); (CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or        lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); particularly        favoured are NR²⁰CO lower alkyl (R²⁰═H; or lower alkyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R¹⁶: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R¹⁷: lower alkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(q)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(q)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(q)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(q)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)₁COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(q)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(r)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(r)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).

Among the building blocks A1 to A69 the following are preferred: A5 withR² being H, A8, A22, A25, A38 with R² being H, A42, A47, and A50. Mostpreferred are building blocks of type A8′:

wherein R²⁰ is H or lower alkyl; and R⁶⁴ is alkyl; alkenyl; aryl;aryl-lower alkyl; or heteroaryl-lower alkyl; especially those whereinR⁶⁴ is n-hexyl (A8′-1); n-heptyl (A8′-2); 4-(phenyl)benzyl (A8′-3);diphenylmethyl (A8′-4); 3-amino-propyl (A8′-5); 5-amino-pentyl (A8′-6);methyl (A8′-7); ethyl (A8′-8); isopropyl (A8′-9); isobutyl (A8′-10);n-propyl (A8′-11); cyclohexyl (A8′-12); cyclohexylmethyl (A8′-13);n-butyl (A8′-14); phenyl (A8′-15); benzyl (A8′-16); (3-indolyl)methyl(A8′-17); 2-(3-indolyl)ethyl (A8′-18); (4-phenyl)phenyl (A8′-19); andn-nonyl (A8′-20).

Building block A70 belongs to the class of open-chain α-substitutedα-amino acids, building blocks A71 and A72 to the corresponding β-aminoacid analogues and building blocks A73-A104 to the cyclic analogues ofA70. Such amino acid derivatives have been shown to constrain smallpeptides in well defined reverse turn or U-shaped conformations (C. M.Venkatachalam, Biopolymers, 1968, 6, 1425-1434; W. Kabsch, C Sander,Biopolymers 1983, 22, 2577). Such building blocks or templates areideally suited for the stabilization of β-hairpin conformations inpeptide loops (D. Obrecht, M. Altorfer, J. A. Robinson, “Novel PeptideMimetic Building Blocks and Strategies for Efficient Lead Finding”, Adv.Med Chem. 1999, Vol. 4, 1-68; P. Balaram, “Non-standard amino acids inpeptide design and protein engineering”, Curr. Opin. Struct. Biol. 1992,2, 845-851; M. Crisma, G. Valle, C. Toniolo, S. Prasad, R. B. Rao, P.Balaram, “β-turn conformations in crystal structures of model peptidescontaining α,α-disubstituted amino acids”, Biopolymers 1995, 35, 1-9; V.J. Hruby, F. Al-Obeidi, W. Kazmierski, Biochem. J. 1990, 268, 249-262).

It has been shown that both enantiomers of building blocks -A70-CO— toA104-CO— in combination with a building block —B—CO— of L-configurationcan efficiently stabilize and induce β-hairpin conformations (D.Obrecht, M. Altorfer, J. A. Robinson, “Novel Peptide Mimetic BuildingBlocks and Strategies for Efficient Lead Finding”, Adv. Med Chem. 1999,Vol. 4, 1-68; D. Obrecht, C. Spiegler, P. Schönholzer, K. Müller, H.Heimgartner, F. Stierli, Helv. Chim. Acta 1992, 75, 1666-1696; D.Obrecht, U. Bohdal, J. Daly, C. Lehmann, P. Schönholzer, K. Müller,Tetrahedron 1995, 51, 10883-10900; D. Obrecht, C. Lehmann, C. Ruffieux,P. Schönholzer, K. Müller, Helv. Chim. Acta 1995, 78, 1567-1587; D.Obrecht, U. Bohdal, C. Broger, D. Bur, C. Lehmann, R. Ruffieux, P.Schönholzer, C. Spiegler, Helv. Chim. Acta 1995, 78, 563-580; D.Obrecht, H. Karajiannis, C. Lehmann, P. Schönholzer, C. Spiegler, Helv.Chim. Acta 1995, 78, 703-714).

Thus, for the purposes of the present invention templates (a1) can alsoconsist of -A70-CO— to A104-CO— where building block A70 to A104 is ofeither (D)- or (L)-configuration, in combination with a building blockB—CO— of (L)-configuration.

Preferred values for R²⁰ in A70 to A104 are H or lower alkyl with methylbeing most preferred. Preferred values for R¹⁸, R¹⁹ and R²¹-R²⁹ inbuilding blocks A70 to A104 are the following:

-   -   R¹⁸: lower alkyl.    -   R¹⁹: lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(p)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(p)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(p)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(o)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R²¹: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        (CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        (CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R²²: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R²³: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        particularly favoured are NR²⁰CO lower alkyl (R²⁰═H; or lower        alkyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower        alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy);    -   R²⁴: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        particularly favoured are NR²⁰CO lower alkyl (R²⁰═H; or lower        alkyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower        alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy);    -   R²⁵: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(s)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower        alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower        alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower        alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R²⁶: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower        alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower        alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower        alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁹)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   Alternatively, R²⁵ and R²⁶ taken together can be —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl).    -   R²⁷: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R²⁸: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R²⁹: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H, or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        particularly favored are NR²⁰CO lower-alkyl (R²⁰═H; or lower        alkyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower        alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).

For templates (b) to (p), such as (b1) and (c1), the preferred valuesfor the various symbols are the following:

-   -   R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵        (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶        (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴        (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower        alkyl; or R³³ and R³⁴ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or        lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o) NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower        alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or        lower alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower        alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower        alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower        alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and        R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R²⁰: H; or lower alkyl.    -   R³⁰: H, methyl.    -   R³¹: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower        alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower        alkyl; or lower alkenyl); (—CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower        alkyl, or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁹)₂ (where R⁶⁹: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(r)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy); most preferred is —CH₂CONR⁵⁸R⁵⁹ (R⁵⁸:        H; or lower alkyl; R⁵⁹: lower alkyl; or lower alkenyl).    -   R³²: H, methyl.    -   R³³: lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(s)NR³⁴R⁶³ (where R³⁴:        lower alkyl; or lower alkenyl; R⁶³: H; or lower alkyl; or R³⁴        and R⁶³ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        (CH₂)_(m)OCONR⁷⁵R⁸² (where R⁷⁵: lower alkyl; or lower alkenyl;        R⁸²: H; or lower alkyl; or R⁷⁵ and R⁸² taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR⁷⁸R⁸² (where R²⁰: H; or lower lower alkyl;        R⁷⁸: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R⁷⁸ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower        alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower        alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower        alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl).    -   R³⁴: H; or lower alkyl.    -   R³⁵: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower        alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower        alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower        alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl).    -   R³⁶: lower alkyl; lower alkenyl; or aryl-lower alkyl.    -   R³⁷: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl);        —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower        alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower        alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower        alkyl, or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alky; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R³⁸: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁸ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower        alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower        alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower        alkyl, or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R³⁹: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where:        R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl).    -   R⁴⁰: lower alkyl; lower alkenyl; or aryl-lower alkyl.    -   R⁴¹: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl);        —(CH₂)_(p) NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower        alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower        alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower        alkyl, or lower alkenyl; and R⁵⁹: H; lower alky; or R⁵⁸ and R⁵⁹        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁴²: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower        alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower        alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower        alkyl, or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁴³: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)₂PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁴⁴: lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(p)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁸ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(p)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or        —(CH₂)_(o)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁴⁵: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(s)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or        —(CH₂)_(s)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁴⁶: H; lower alkyl; lower alkenyl; —(CH₂)_(s)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(s)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(s)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(s)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(s)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(s)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or        —(CH₂)_(s)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁴⁷: H; or OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl).    -   R⁴⁸: H; or lower alkyl.    -   R⁴⁹: H; lower alkyl; —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl;        or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl;        or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken        together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or        (CH₂)_(s)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁵⁰: H; methyl.    -   R⁵¹: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        (CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower        alkyl; or lower alkenyl); —(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower        alkyl; or lower alkenyl); —(CH₂)_(p)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower        alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹        taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or        —(CH₂)_(r)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁵²: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; R⁵⁷: H;        or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower        alkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(p)COOR⁵⁷        (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(p)CONR⁵⁸R⁵⁹        (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower        alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or        —(CH₂)_(r)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁵³: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R⁸² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower        alkyl; or lower alkenyl); —(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower        alkyl; or lower alkenyl); —(CH₂)_(p)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower        alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹        taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); or —(CH₂)_(r)C₆H₄R⁸ (where R⁸: H; F; Cl;CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

-   -   R⁵⁴: lower alkyl; lower alkenyl; or aryl-lower alkyl.

Among the building blocks A70 to A104 the following are preferred: A74with R²² being H, A75, A76, A77 with R²² being H, A78 and A79.

The building block —B—CO— within templates (a1) and (a2) designates anL-amino acid residue. Preferred values for B are: —NR²⁰CH(R⁷¹)— andenantiomers of groups A5 with R² being H, A8, A22, A25, A38 with R²being H, A42, A47, and A50. Most preferred are

Ala L-Alanine Arg L-Arginine Asn L-Asparagine Cys L-Cysteine GlnL-Glutamine Gly Glycine His L-Histidine Ile L-Isoleucine Leu L-LeucineLys L-Lysine Met L-Methionine Phe L-Phenylalanine Pro L-ProlinePro(5RPhe) (2S,5R)-5-phenylpyrrrolidine-2-carbocyclic acid Ser L-SerineThr L-Threonine Trp L-Tryptophan Tyr L-Tyrosine Val L-Valine CitL-Citrulline Orn L-Ornithine tBuA L-t-Butylalanine Sar Sarcosine t-BuGL-tert.-Butylglycine 4AmPhe L-para-Aminophenylalanine 3AmPheL-meta-Aminophenylalanine 2AmPhe L-ortho-AminophenylalaninePhe(mC(NH₂)═NH) L-meta-Amidinophenylalanine Phe(pC(NH₂)═NH)L-para-Amidinophenylalanine Phe(mNHC (NH₂)═NH)L-meta-Guanidinophenylalanine Phe(pNHC (NH₂)═NH)L-para-Guanidinophenylalanine Phg L-Phenylglycine ChaL-Cyclohexylalanine C₄al L-3-Cyclobutylalanine C₅alL-3-Cyclopentylalanine Nle L-Norleucine 2-Nal L-2-Naphthylalanine 1-NalL-1-Naphthylalanine 4Cl-Phe L-4-Chlorophenylalanine 3Cl-PheL-3-Chlorophenylalanine 2Cl-Phe L-2-Chlorophenylalanine 3,4Cl₂•PheL-3,4-Dichlorophenylalanine 4F-Phe L-4-Fluorophenylalanine 3F-PheL-3-Fluorophenylalanine 2F-Phe L-2-Fluorophenylalanine TicL-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid ThiL-β-2-Thienylalanine Tza L-2-Thiazolylalanine Mso L-Methionine sulfoxideAcLys L-N-Acetyllysine Dpr L-2,3-Diaminopropionic acid A₂BuL-2,4-Diaminobutyric acid Dbu (S)-2,3-Diaminobutyric acid Abuγ-Aminobutyric acid (GABA) Aha ε-Aminohexanoic acid Aibα-Aminoisobutyric acid Y(Bzl) L-O-Benzyltyrosine Bip L-BiphenylalanineS(Bzl) L-O-Benzylserine T(Bzl) L-O-Benzylthreonine hChaL-Homo-cyclohexylalanine hCys L-Homo-cysteine hSer L-Homo-serine hArgL-Homo-arginine hPhe L-Homo-phenylalanine Bpa L-4-BenzoylphenylalaninePip L-Pipecolic acid OctG L-Octylglycine MePhe L-N-MethylphenylalanineMeNle L-N-Methylnorleucine MeAla L-N-Methylalanine MeIleL-N-Methylisoleucine MeVal L-N-Methvaline MeLeu L-N-Methylleucine

In addition, the most preferred values for B also include groups of typeA8″ of (L)-configuration:

-   -   wherein R²⁰ is H or lower alkyl and R⁶⁴ is alkyl; alkenyl;        —[(CH₂)_(u)—X]_(t)—CH₃ (where X is —O—; —NR²⁰—, or —S—; u=1-3,        and t=1-6), aryl; aryl-lower alkyl; or heteroaryl-lower alkyl;        especially those wherein R⁶⁴ is n-hexyl (A8″-21); n-heptyl        (A8″-22); 4-(phenyl)benzyl (A8″-23); diphenylmethyl (A8″-24);        3-amino-propyl (A8″-25); 5-amino-pentyl (A8″-26); methyl        (A8″-27); ethyl (A8″-28); isopropyl (A8″-29); isobutyl (A8″-30);        n-propyl (A8″-31); cyclohexyl (A8″-32); cyclohexylmethyl        (A8″-33); n-butyl (A8″-34); phenyl (A8″-35); benzyl (A8″-36);        (3-indolyl)methyl (A8″-37); 2-(3-indolyl)ethyl (A8″-38);        (4-phenyl)phenyl (A8″-39); n-nonyl (A8″-40); CH₃—OCH₂CH₂—OCH₂—        (A8″-41) and CH₃—(OCH₂CH₂)₂—OCH₂— (A8″-42).

The peptidic chain Z of the β-hairpin mimetics described herein isgenerally defined in terms of amino acid residues belonging to one ofthe following groups:

-   -   Group C —NR²⁰CH(R⁷²)CO—; “hydrophobic: small to medium-sized”    -   Group D —NR²⁰CH(R⁷³)CO—; “hydrophobic: large aromatic or        heteroaromatic”    -   Group E —NR²⁰CH(R⁷⁴)CO—; “polar-cationic” and “urea-derived”    -   Group F —NR²⁰CH(R⁸⁴)CO—; “polar-non-charged or anionic”    -   Group H —NR²⁰—CH(CO—)—(CH₂)₄₋₇—CH(CO—)—NR²⁰—;        —NR²⁰—CH(CO—)—(CH₂)_(p)SS(CH₂)_(p)—CH(CO—)—NR²⁰—;        —NR²⁰—CH(CO—)—(—(CH₂)_(p)NR²⁰CO(CH₂)_(p)—CH(CO—)—NR²⁰—; and        —NR²⁰—CH(CO—)—(—(CH₂)_(p)NR²⁰CONR²⁰(CH₂)_(p)—CH(CO—)—NR²⁰—;        “interstrand linkage”

Furthermore, the amino acid residues in chain Z can also be of formula-A-CO— or of formula —B—CO— wherein A and B are as defined above.Finally, Gly can also be an amino acid residue in chain Z, and Pro canbe an amino acid residue in chain Z, too, with the exception ofpositions where interstrand linkages (H) are possible.

Group C comprises amino acid residues with small to medium-sizedhydrophobic side chain groups according to the general definition forsubstituent R⁷². A hydrophobic residue refers to an amino acid sidechain that is uncharged at physiological pH and that is repelled byaqueous solution. Furthermore these side chains generally do not containhydrogen bond donor groups, such as (but not limited to) primary andsecondary amides, primary and secondary amines and the correspondingprotonated salts thereof, thiols, alcohols, phosphonates, phosphates,ureas or thioureas. However, they may contain hydrogen bond acceptorgroups such as ethers, thioethers, esters, tertiary amides, alkyl- oraryl phosphonates and phosphates or tertiary amines. Genetically encodedsmall-to-medium-sized amino acids include alanine, isoleucine, leucine,methionine and valine.

Group D comprises amino acid residues with aromatic and heteroaromaticside chain groups according to the general definition for substituentR⁷³. An aromatic amino acid residue refers to a hydrophobic amino acidhaving a side chain containing at least one ring having a conjugatedπ-electron system (aromatic group). In addition they may containhydrogen bond donor groups such as (but not limited to) primary andsecondary amides, primary and secondary amines and the correspondingprotonated salts thereof, thiols, alcohols, phosphonates, phosphates,ureas or thioureas, and hydrogen bond acceptor groups such as (but notlimited to) ethers, thioethers, esters, tetriary amides, alkyl- or arylphosphonates -and phosphates or tertiary amines. Genetically encodedaromatic amino acids include phenylalanine and tyrosine.

A heteroaromatic amino acid residue refers to a hydrophobic amino acidhaving a side chain containing at least one ring having a conjugatedn-system incorporating at least one heteroatom such as (but not limitedto) O, S and N according to the general definition for substituent R⁷⁷.In addition such residues may contain hydrogen bond donor groups such as(but not limited to) primary and secondary amides, primary and secondaryamines and the corresponding protonated salts thereof, thiols, alcohols,phosphonates, phosphates, ureas or thioureas, and hydrogen bond acceptorgroups such as (but not limited to) ethers, thioethers, esters, tetriaryamides, alkyl- or aryl phosphonates -and phosphates or tertiary amines.Genetically encoded heteroaromatic amino acids include tryptophan andhistidine.

Group E comprises amino acids containing side chains withpolar-cationic, acylamino- and urea-derived residues according to thegeneral definition for substituent R⁷⁴. Polar-cationic refers to a basicside chain which is protonated at physiological pH. Genetically encodedpolar-cationic amino acids include arginine, lysine and histidine.Citrulline is an example for an urea derived amino acid residue.

Group F comprises amino acids containing side chains withpolar-non-charged or anionic residues according to the generaldefinition for substituent R⁸⁴. A polar-non-charged or anionic residuerefers to a hydrophilic side chain that is uncharged and, respectivelyanionic at physiological pH (carboxylic acids being included), but thatis not repelled by aqueous solutions. Such side chains typically containhydrogen bond donor groups such as (but not limited to) primary andsecondary amides, carboxyclic acids and esters, primary and secondaryamines, thiols, alcohols, phosphonates, phosphates, ureas or thioureas.These groups can form hydrogen bond networks with water molecules. Inaddition they may also contain hydrogen bond acceptor groups such as(but not limited to) ethers, thioethers, esters, tetriary amides,carboxylic acids and carboxylates, alkyl- or aryl phosphonates -andphosphates or tertiary amines. Genetically encoded polar-non-chargedamino acids include asparagine, cysteine, glutamine, serine andthreonine, but also aspartic acid and glutamic acid.

Group H comprises side chains of preferably (L)-amino acids at oppositepositions of the β-strand region that can form an interstrand linkage.The most widely known linkage is the disulfide bridge formed bycysteines and homo-cysteines positioned at opposite positions of theβ-strand. Various methods are known to form disulfide linkages includingthose described by: J. P. Tam et al. Synthesis 1979, 955-957; Stewart etal., Solid Phase Peptide Synthesis, 2d Ed., Pierce Chemical Company,III., 1984; Ahmed et al. J. Biol. Chem. 1975, 250, 8477-8482; andPennington et al., Peptides, pages 164-166, Giralt and Andreu, Eds.,ESCOM Leiden, The Netherlands, 1990. Most advantageously, for the scopeof the present invention, disulfide linkages can be prepared usingacetamidomethyl (Acm)-protective groups for cysteine. A well establishedinterstrand linkage consists in linking ornithines and lysines,respectively, with glutamic and aspartic acid residues located atopposite β-strand positions by means of an amide bond formation.Preferred protective groups for the side chain amino-groups of ornithineand lysine are allyloxycarbonyl (Alloc) and allylesters for aspartic andglutamic acid. Finally, interstrand linkages can also be established bylinking the amino groups of lysine and ornithine located at oppositeβ-strand positions with reagents such as N,N-carbonylimidazole to formcyclic ureas.

As mentioned earlier, positions for interstrand linkages are positionsP4 and P 9 and/or P2 and P11 taken together. Such interstrand linkagesare known to stabilize the β-hairpin conformations and thus constitutean important structural element for the design of β-hairpin mimetics.

Most preferred amino acid residues in chain Z are those derived fromnatural α-amino acids. Hereinafter follows a list of amino acids which,or the residues of which, are suitable for the purposes of the presentinvention, the abbreviations corresponding to generally adopted usualpractice:

three letter code one letter code Ala L-Alanine A Arg L-Arginine R AsnL-Asparagine N Asp L-Aspartic acid D Cys L-Cysteine C Glu L-Glutamicacid E Gln L-Glutamine Q Gly Glycine G His L-Histidine H IleL-Isoleucine I Leu L-Leucine L Lys L-Lysine K Met L-Methionine M PheL-Phenylalanine F Pro L-Proline P ^(D)Pro D-Proline ^(D)P Ser L-Serine SThr L-Threonine T Trp L-Tryptophan W Tyr L-Tyrosine Y Val L-Valine VOther α-amino acids which, or the residues of which, are suitable forthe purposes of the present invention include:

Cit L-Citrulline Orn L-Ornithine tBuA L-t-Butylalanine Sar Sarcosine PenL-Penicillamine t-BuG L-tert.-Butylglycine 4AmPheL-para-Aminophenylalanine 3AmPhe L-meta-Aminophenylalanine 2AmPheL-ortho-Aminophenylalanine Phe(mC(NH₂)═NH) L-meta-AmidinophenylalaninePhe(pC(NH₂)═NH) L-para-Amidinophenylalanine Phe(mNHC (NH₂)═NH)L-meta-Guanidinophenylalanine Phe(pNHC (NH₂)═NH)L-para-Guanidinophenylalanine Phg L-Phenylglycine ChaL-Cyclohexylalanine C₄al L-3-Cyclobutylalanine C₅alL-3-Cyclopentylalanine Nle L-Norleucine 2-Nal L-2-Naphthylalanine 1-NalL-1-Naphthylalanine 4Cl-Phe L-4-Chlorophenylalanine 3Cl-PheL-3-Chlorophenylalanine 2Cl-Phe L-2-Chlorophenylalanine 3,4Cl₂-PheL-3,4-Dichlorophenylalanine 4F-Phe L-4-Fluorophenylalanine 3F-PheL-3-Fluorophenylalanine 2F-Phe L-2-Fluorophenylalanine Tic1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid ThiL-β-2-Thienylalanine Tza L-2-Thiazolylalanine Mso L-Methionine sulfoxideAcLys N-Acetyllysine Dpr 2,3-Diaminopropionic acid A₂Bu2,4-Diaminobutyric acid Dbu (S)-2,3-Diaminobutyric acid Abuγ-Aminobutyric acid (GABA) Aha ε-Aminohexanoic acid Aibα-Aminoisobutyric acid Y(Bzl) L-O-Benzyltyrosine BipL-(4-phenyl)phenylalanine S(Bzl) L-O-Benzylserine T(Bzl)L-O-Benzylthreonine hCha L-Homo-cyclohexylalanine hCys L-Homo-cysteinehSer L-Homo-serine hArg L-Homo-arginine hPhe L-Homo-phenylalanine BpaL-4-Benzoylphenylalanine 4-AmPyrr1(2S,4S)-4-Amino-pyrrolidine-L-carboxylic acid 4-AmPyrr2(2S,4R)-4-Amino-pyrrolidine-L-carboxylic acid 4-PhePyrr1(2S,5R)-4-Phenyl-pyrrolidine-L-carboxylic acid 4-PhePyrr2(2S,5S)-4-Phenyl-pyrrolidine-L-carboxylic acid 5-PhePyrr1(2S,5R)-5-Phenyl-pyrrolidine-L-carboxylic acid 5-PhePyrr2(2S,5S)-5-Phenyl-pyrrolidine-L-carboxylic acid Pro(4-OH)1(4S)-L-Hydroxyproline Pro(4-OH)2 (4R)-L-Hydroxyproline Pip L-Pipecolicacid ^(D)Pip D-Pipecolic acid OctG L-Octylglycine NGly N-MethylglycineMePhe L-N-Methylphenylalanine MeNle L-N-Methylnorleucine MeAlaL-N-Methylalanine MeIle L-N-Methylisoleucine MeVal L-N-MethylvalineMeLeu L-N-Methylleucine DimK L-(N′,N′Dimethyl)-lysine Lpzp L-Piperazinicacid Dpzp D-Piperazinic acid Isorn L-(N′,N′-diisobutyl)-ornithine PipAlaL-2-(4′-piperidinyl)-alanine PirrAla L-2-(3′-pyrrolidinyl)-alanine Ampc4-Amino-piperidine-4-carboxylic acid NMeR L-N-Methylarginine NMeKL-N-Methyllysine NMePhe L-N-Methylphenylalanine IPegKL-2-Amino-6-{2-[2-(2-methoxy- ethoxy)ethoxy]acetylamino}-hexanoic acidSPegK L-2-Amino-6-[2-(2methoxy-ethoxy)- acetylamino]-hexanoic acid DabL-2,4-Diamino-butyric acid IPegDab L-2-Amino-4{2-[2-(2-methoxy-ethoxy)-ethoxy]-acetylamino}-butyric acid SPegDabL-2-Amino-4[2-(2-methoxy-ethoxy)- acetylamino] butyric acid 4-PyrAlaL-2-(4′Pyridyl)-alanine OrnPyr L-2-Amino-5-[(2′carbonylpyrazine)]amino-pentanoic acid BnG N-Benzylglycine AlloT Allo-Threonin Aoc2-(S)-Aminooctanoic acid Cpa L-Cyclo-Propylalanine

Particularly preferred residues for group C are:

Ala L-Alanine Ile L-Isoleucine Leu L-Leucine Met L-Methionine ValL-Valine tBuA L-t-Butylalanine t-BuG L-tert.-Butylglycine ChaL-Cyclohexylalanine C₄al L-3-Cyclobutylalanine C₅alL-3-Cyclopentylalanine Nle L-Norleucine hCha L-Homo-cyclohexylalanineOctG L-Octylglycine MePhe L-N-Methylphenylalanine MeNleL-N-Methylnorleucine MeAla L-N-Methylalanine MeIle L-N-MethylisoleucineMeVal L-N-Methylvaline MeLeu L-N-Methylleucine Aoc 2-(S)-Aminooctanoicacid Cpa L-Cyclo-Propylalanine

Particularly preferred residues for group D are:

His L-Histidine Phe L-Phenylalanine Trp L-Tryptophan Tyr L-Tyrosine PhgL-Phenylglycine 2-Nal L-2-Naphthylalanine 1-Nal L-1-Naphthylalanine4Cl-Phe L-4-Chlorophenylalanine 3Cl-Phe L-3-Chlorophenylalanine 2Cl-PheL-2-Chlorophenylalanine 3,4Cl₂-Phe L-3,4-Dichlorophenylalanine 4F-PheL-4-Fluorophenylalanine 3F-Phe L-3-Fluorophenylalanine 2F-PheL-2-Fluorophenylalanine Thi L-β-2-Thienylalanine TzaL-2-Thiazolylalanine Y(Bzl) L-O-Benzyltyrosine Bip L-BiphenylalanineS(Bzl) L-O-Benzylserine T(Bzl) L-O-Benzylthreonine hPheL-Homo-phenylalanine Bpa L-4-Benzoylphenylalanine PirrAlaL-2-(3′-pyrrolidinyl)-alanine NMePhe L-N-Methylphenylalanine 4-PyrAlaL-2-(4Tyridyl)-alanine

Particularly preferred residues for group E are

Arg L-Arginine Lys L-Lysine Orn L-Ornithine Dpr L-2,3-Diaminopropionicacid A₂Bu L-2,4-Diaminobutyric acid Dbu (S)-2,3-Diaminobutyric acidPhe(pNH₂) L-para-Aminophenylalanine Phe(mNH₂) L-meta-AminophenylalaninePhe(oNH₂) L-ortho-Aminophenylalanine hArg L-Homo-argininePhe(mC(NH₂)═NH) L-meta-Amidinophenylalanine Phe(pC(NH₂)═NH)L-para-Amidinophenylalanine Phe(mNHC (NH₂)═NH)L-meta-Guanidinophenylalanine Phe(pNHC (NH₂)═NH)L-para-Guanidinophenylalanine DimK L-(N′,N′Dimethyl)-lysine IsornL-(N′,N′-diisobutyl)-ornithine NMeR L-N-Methylarginine NMeKL-N-Methyllysine IPegK L-2-Amino-6-{2-[2-(2-methoxy-ethoxy)ethoxy]acetylamino}-hexanoic acid SPegKL-2-Amino-6-[2-(2methoxy-ethoxy)- acetylamino]-hexanoic acid DabL-2,4-Diamino-butyric acid IPegDab L-2-Amino-4{2-[2-(2-methoxy-ethoxy)-ethoxy]-acetylamino}-butyric acid SPegDabL-2-Amino-4[2-(2-methoxy-ethoxy)- acetylamino] butyric acid OrnPyrL-2-Amino-5- [(2′carbonylpyrazine)]aminopentanoic PipAlaL-2-(4′-piperidinyl)-alanine

Particularly preferred residues for group F are

Asn L-Asparagine Asp L-Aspartic acid Cys L-Cysteine Gln L-Glutamine GluL-Glutamic acid Ser L-Serine Thr L-Threonine AlloThr Allo Threonine CitL-Citrulline Pen L-Penicillamine AcLys L-N^(ε)-Acetyllysine hCysL-Homo-cysteine hSer L-Homo-serine

Generally, the peptidic chain Z within the β-hairpin mimetics of theinvention comprises 12 amino acid residues. The positions P1 to P12 ofeach amino acid residue in the chain Z are unequivocally defined asfollows: P1 represents the first amino acid in the chain Z that iscoupled with its N-terminus to the C-terminus of the templates (b)-(p),or of group —B—CO— in template (a1), or of group -A-CO— in template(a2); and P12 represents the last amino acid in the chain Z that iscoupled with its C-terminus to the N-terminus of the templates (b)-(p),or of group -A-CO— in template (a1), or of group —B—CO— in template(a2). Each of the positions P1 to P12 will preferably contain an aminoacid residue belonging to one of the above types C, D, E, F, H, or offormula -A-CO— or of formula —B—CO—, or being Gly, or Pro as follows:

The α-amino acid residues in positions 1 to 12 of the chain Z arepreferably:

-   -   P1: of type C or of type D or of type E or of type F;    -   P2: of type D;    -   P3: of type C, or the residue is Gly or Pro;    -   P4: of type C or of type E or of type F, or the residue is Gly        or Pro;    -   P5: of type E, or the residue is Gly or Pro;    -   P6: of type E, of type C or of type F or of formula A-CO—, or        the residue is Gly or Pro;    -   P7: of type C or of type E or of type F or of formula —B—CO—;    -   P8: of type D, or of type F;    -   P9: of type E or of type F or of type C;    -   P10: of type E;    -   P11: of type F or of type C, or the residue is Gly or Pro; and    -   P12: of type C or of type D or of type E, or of type F; or    -   P4 and P9 and/or P2 and P11, taken together, can form a group of        type H; and    -   at P6, P10 and P11 also D-isomers being possible;        or, alternatively, within the less preferred embodiment        mentioned earlier herein above:    -   P1: of type C or of type D or of type E, or of type F;    -   P2: of type F or of type C, or the residue is Gly or Pro;    -   P3: of type E;    -   P4: of type E or of type F or of type C;    -   P5: of type D, or of Type F;    -   P6: of type C or of type E or of type F or of formula —B—CO—;    -   P7: of type C or of type F or of formula A-CO—, or the residue        is Gly or Pro;    -   P8: of type E, or the residue is Gly or Pro;    -   P9: of type C or of type E or of type F, or the residue is Gly        or Pro;    -   P10: of type C, or the residue is Gly or Pro;    -   P11: of type D; and    -   P12: of type C or of type D or of type E or of type F; or    -   P4 and P9 and/or P2 and P11, taken together, can form a group of        type H; and    -   at P2, P3, and P7 also D-isomers being possible.

If n is 12, the α-amino acid residues in positions 1 to 12 are mostpreferably:

-   -   P1: Ala, Cit, Thr, Thr, Asp, Glu;    -   P2: Trp, Tyr;    -   P3: Ile, Val, Nle, Chg, Cha;    -   P4: Dab, Lys, Gln;    -   P5: Lys, Dab, Orn;    -   P6: Dab, ^(D)Dab; Lys;    -   P7: His, Lys, Gln, Dab;    -   P8: Tyr, Trp, Ser;    -   P9 Dab, Lys;    -   P10: Dab, Lys;    -   P11: Ala, Abu, Thr, Gly, Pro, Hse, Ile, Nva, ^(D)Ala, ^(D)Val,        Aib, Nle, Chg, Cha, Gln, Asp, Glu, Cpa, t-BuG, Leu, Val, Asn;    -   P12: Dab, Lys, Gln, Ser; at P6, P10 and P11 are D-Isomers being        possible.

Particularly preferred β-hairpin peptidomimetics of the inventioninclude those described in Examples 1, 2, 6, 16, 19, 22, 24, 25, 28, 29,32, 35, 40, 41, 49, 50.

The processes of the invention can advantageously be carried out asparallel array syntheses to yield libraries of template-fixed β-hairpinpeptidomimetics of the above general formula I. Such parallel synthesesallow one to obtain arrays of numerous (normally 24 to 192, typically96) compounds of general formula I in high yields and defined purities,minimizing the formation of dimeric and polymeric by-products. Theproper choice of the functionalized solid-support (i.e. solid supportplus linker molecule), templates and site of cyclization play therebykey roles.

The functionalized solid support is conveniently derived frompolystyrene crosslinked with, preferably 1-5%, divinylbenzene;polystyrene coated with polyethyleneglycol spacers (Tentagel®); andpolyacrylamide resins (see also Obrecht, D.; Villalgordo, J.-M,“Solid-Supported Combinatorial and Parallel Synthesis ofSmall-Molecular-Weight Compound Libraries”, Tetrahedron OrganicChemistry Series, Vol. 17, Pergamon, Elsevier Science, 1998).

The solid support is functionalized by means of a linker, i.e. abifunctional spacer molecule which contains on one end an anchoringgroup for attachment to the solid support and on the other end aselectively cleavable functional group used for the subsequent chemicaltransformations and cleavage procedures. For the purposes of the presentinvention two types of linkers are used:

Type 1 linkers are designed to release the amide group under acidicconditions (Rink H, Tetrahedron Lett. 1987, 28, 3783-3790). Linkers ofthis kind form amides of the carboxyl group of the amino acids; examplesof resins functionalized by such linker structures include4-[(((2,4-dimethoxyphenyl)Fmoc-aminomethyl)phenoxyacetamido)aminomethyl]PS resin,4-[(((2,4-dimethoxyphenyl)Fmoc-aminomethyl)phenoxyacetamido)aminomethyl]-4-methylbenzydrylaminePS resin (Rink amide MBNA PS Resin), and4-[(((2,4-dimethoxyphenyl)Fmoc-aminomethyl)phenoxyacetamido)aminomethyl]benzhydrylaminePS-resin (Rink amide BHA PS resin). Preferably, the support is derivedfrom polystyrene crosslinked with, most preferably 1-5%, divinylbenzeneand functionalized by means of the4-(((2,4-dimethoxyphenyl)Fmoc-aminomethyl)phenoxyacetamido) linker.

Type 2 linkers are designed to eventually release the carboxyl groupunder acidic conditions. Linkers of this kind form acid-labile esterswith the carboxyl group of the amino acids, usually acid-labile benzyl,benzhydryl and trityl esters; examples of such linker structures include2-methoxy-4-hydroxymethylphenoxy (Sasrin® linker),4-(2,4-dimethoxyphenyl-hydroxymethyl)-phenoxy (Rink linker),4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid (HMPB linker), trityland 2-chlorotrityl. Preferably, the support is derived from polystyrenecrosslinked with, most preferably 1-5%, divinylbenzene andfunctionalized by means of the 2-chlorotrityl linker.

When carried out as parallel array syntheses the processes of theinvention can be advantageously carried out as described herein belowbut it will be immediately apparent to those skilled in the art howthese procedures will have to be modified in case it is desired tosynthesize one single compound of the above formula I.

A number of reaction vessels (normally 24 to 192, typically 96), equalto the total number of compounds to be synthesized by the parallelmethod, are loaded with 25 to 1000 mg, preferably 100 mg, of theappropriate functionalized solid support, preferably 1 to 3%cross-linked polystyrene or Tentagel resin.

The solvent to be used must be capable of swelling the resin andincludes, but is not limited to, dichloromethane (DCM),dimethylformamide (DMF), N-methylpyrrolidone (NMP), dioxane, toluene,tetrahydrofuran (THF), ethanol (EtOH), trifluoroethanol (TFE),isopropylalcohol and the like. Solvent mixtures containing as at leastone component a polar solvent (e.g. 20% TFE/DCM, 35% THF/NMP) arebeneficial for ensuring high reactivity and solvation of the resin-boundpeptide chains (Fields, G. B., Fields, C. G., J. Am. Chem. Soc. 1991,113, 4202-4207).

With the development of various linkers that release the C-terminalcarboxylic acid group under mild acidic conditions, not affectingacid-labile groups protecting functional groups in the side chain(s),considerable progresses have been made in the synthesis of protectedpeptide fragments. The 2-methoxy-4-hydroxybenzylalcohol-derived linker(Sasrin® linker, Mergler et al., Tetrahedron Lett. 1988, 29 4005-4008)is cleavable with diluted trifluoroacetic acid (0.5-1% TFA in DCM) andis stable to Fmoc deprotection conditions during the peptide synthesis,Boc/tBu-based additional protecting groups being compatible with thisprotection scheme. Other linkers which are suitable for the process ofthe invention include the super acid labile4-(2,4-dimethoxyphenyl-hydroxymethyl)-phenoxy linker (Rink linker, Rink,H. Tetrahedron Lett. 1987, 28, 3787-3790), where the removal of thepeptide requires 10% acetic acid in DCM or 0.2% trifluoroacetic acid inDCM; the 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid-derived linker(HMPB-linker, Florsheimer & Riniker, Peptides 1991, 1990 131) which isalso cleaved with 1% TFA/DCM in order to yield a peptide fragmentcontaining all acid labile side-chain protective groups; and, inparticular, the 2-chlorotritylchloride linker (Barbs et al., TetrahedronLett. 1989, 30, 3943-3946), which allows the peptide detachment using amixture of glacial acetic acid/trifluoroethanol/DCM (1:2:7) for 30 min.

Suitable protecting groups for amino acids and, respectively, for theirresidues are, for example,

-   -   for the amino group (as is present e.g. also in the side-chain        of lysine)

Cbz benzyloxycarbonyl Boc tert.-butyloxycarbonyl Fmoc9-fluorenylmethoxycarbonyl Alloc allyloxycarbonyl Teoctrimethylsilylethoxycarbonyl Tcc trichloroethoxycarbonyl Npso-nitrophenylsulfonyl; Trt triphenymethyl or trityl

-   -   for the carboxyl group (as is present e.g. also in the        side-chain of aspartic and glutamic acid) by conversion into        esters with the alcohol components

tBu tert.-butyl Bn benzyl Me methyl Ph phenyl Pac Phenacyl Allyl Tsetrimethylsilylethyl Tce trichloroethyl;

-   -   for the guanidino group (as is present e.g. in the side-chain of        arginine)

Pmc 2,2,5,7,8-pentamethylchroman-6-sulfonyl Ts tosyl (i.e.p-toluenesulfonyl) Cbz benzyloxycarbonyl Pbfpentamethyldihydrobenzofuran-5-sulfonyl

-   -   for the hydroxy group (as is present e.g. in the side-chain of        threonine and    -   serine)

tBu tert.-butyl Bn benzyl Trt trityl

-   -   and for the mercapto group (as is present e.g. in the side-chain        of cysteine)

Acm acetamidomethyl tBu tert.-butyl Bn benzyl Trt trityl Mtr4-methoxytrityl.

The 9-fluorenylmethoxycarbonyl-(Fmoc)-protected amino acid derivativesare preferably used as the building blocks for the construction of thetemplate-fixed β-hairpin loop mimetics of formula I. For thedeprotection, i.e. cleaving off of the Fmoc group, 20% piperidine in DMFor 2% DBU/2% piperidine in DMF can be used.

The quantity of the reactant, i.e. of the amino acid derivative, isusually 1 to 20 equivalents based on the milliequivalents per gram(meq/g) loading of the functionalized solid support (typically 0.1 to2.85 meq/g for polystyrene resins) originally weighed into the reactiontube. Additional equivalents of reactants can be used, if required, todrive the reaction to completion in a reasonable time. The reactiontubes, in combination with the holder block and the manifold, arereinserted into the reservoir block and the apparatus is fastenedtogether. Gas flow through the manifold is initiated to provide acontrolled environment, for example, nitrogen, argon, air and the like.The gas flow may also be heated or chilled prior to flow through themanifold. Heating or cooling of the reaction wells is achieved byheating the reaction block or cooling externally with isopropanol/dryice and the like to bring about the desired synthetic reactions.Agitation is achieved by shaking or magnetic stirring (within thereaction tube). The preferred workstations (without, however, beinglimited thereto) are Labsource's Combi-chem station and MultiSynTech's-Syro synthesizer.

Amide bond formation requires the activation of the α-carboxyl group forthe acylation step. When this activation is being carried out by meansof the commonly used carbodiimides such as dicyclohexylcarbodiimide(DCC, Sheehan & Hess, J. Am. Chem. Soc. 1955, 77, 1067-1068) ordiisopropylcarbodiimide (DIC, Sarantakis et al Biochem. Biophys. Res.Commun. 1976, 73, 336-342), the resulting dicyclohexylurea anddiisopropylurea is insoluble and, respectively, soluble in the solventsgenerally used. In a variation of the carbodiimide method1-hydroxybenzotriazole (HOBt, König & Geiger, Chem. Ber 1970, 103,788-798) is included as an additive to the coupling mixture. HOBtprevents dehydration, suppresses racemization of the activated aminoacids and acts as a catalyst to improve the sluggish coupling reactions.Certain phosphonium reagents have been used as direct coupling reagents,such as benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (BOP, Castro et al., Tetrahedron Lett. 1975, 14,1219-1222; Synthesis, 1976, 751-752), orbenzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexaflurophoshate(Py-BOP, Coste et al., Tetrahedron Lett. 1990, 31, 205-208), or2-(1H-benzotriazol-1-yl-)1,1,3,3-tetramethyluronium terafluoroborate(TBTU), or hexafluorophosphate (HBTU, Knorr et al., Tetrahedron Lett.1989, 30, 1927-1930), or1-benzotriazol-1-[bis(dimethylamino)methylene]-5-chloro-hexafluorophosphate-1,3-oxide(HCTU); these phosphonium reagents are also suitable for in situformation of HOBt esters with the protected amino acid derivatives. Morerecently diphenoxyphosphoryl azide (DPPA) orO-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TATU) orO-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU)/7-aza-1-hydroxy benzotriazole (HOAt, Carpinoet al., Tetrahedron Lett. 1994, 35, 2279-2281) have also been used ascoupling reagents.

Due to the fact that near-quantitative coupling reactions are essential,it is desirable to have experimental evidence for completion of thereactions. The ninhydrin test (Kaiser et al., Anal. Biochemistry 1970,34, 595), where a positive colorimetric response to an aliquot ofresin-bound peptide indicates qualitatively the presence of the primaryamine, can easily and quickly be performed after each coupling step.Fmoc chemistry allows the spectrophotometric detection of the Fmocchromophore when it is released with the base (Meienhofer et al., Int.J. Peptide Protein Res. 1979, 13, 35-42).

The resin-bound intermediate within each reaction tube is washed free ofexcess of retained reagents, of solvents, and of by-products byrepetitive exposure to pure solvent(s) by one of the two followingmethods:

1) The reaction wells are filled with solvent (preferably 5 ml), thereaction tubes, in combination with the holder block and manifold, areimmersed and agitated for 5 to 300 minutes, preferably 15 minutes, anddrained by gravity followed by gas pressure applied through the manifoldinlet (while closing the outlet) to expel the solvent;2) The manifold is removed from the holder block, aliquots of solvent(preferably 5 ml) are dispensed through the top of the reaction tubesand drained by gravity through a filter into a receiving vessel such asa test tube or vial.

Both of the above washing procedures are repeated up to about 50 times(preferably about 10 times), monitoring the efficiency of reagent,solvent and by-product removal by methods such as TLC, GC, or inspectionof the washings.

The above described procedure of reacting the resin-bound compound withreagents within the reaction wells followed by removal of excessreagents, by-products and solvents is repeated with each successivetransformation until the final resin-bound fully protected linearpeptide has been obtained.

Before this fully protected linear peptide is detached from the solidsupport, it is possible, if desired, to selectively deprotect one orseveral protected functional group(s) present in the molecule and toappropriately substitute the reactive group(s) thus liberated. To thiseffect, the functional group(s) in question must initially be protectedby a protecting group which can be selectively removed without affectingthe remaining protecting groups present. Alloc (allyloxycarbonyl) is anexample for such an amino protecting group which can be selectivelyremoved, e.g. by means of Pd° and phenylsilane in CH₂Cl₂, withoutaffecting the remaining protecting groups, such as Fmoc, present in themolecule. The reactive group thus liberated can then be treated with anagent suitable for introducing the desired substituent. Thus, forexample, an amino group can be acylated by means of an acylating agentcorresponding to the acyl substituent to be introduced. For theformation of pegylated amino acids such as IPegK, or SPegK, preferably asolution of 5 equivalents of HATU(N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide) in dry DMF and a solution of 10 equivalentsof DIPEA (Diisopropyl ethaylamine) in dry DMF and 5 equivalents of2-[2-(2-methoxyethoxy)ethoxy]acetic acid (lPeg) and, respectively,2-(2-methoxyethoxy)acetic acid (sPeg), is applied to the liberated aminogroup of the appropriate amino acid side chain for 3 h. The procedure isthereafter repeated for another 3 h with a fresh solution of reagentsafter filtering and washing the resin.

Before this fully protected linear peptide is detached from the solidsupport, it is also possible, if desired, to form (an) interstrandlinkage(s) between side-chains of appropriate amino acid residues atopposite positions of the β-strand region.

Interstrand linkages and their formation have been discussed above, inconnection with the explanations made regarding groups of the type Hwhich can, for example, be disulfide bridges formed by cysteine andhomocysteine residues at opposite positions of the β-strand; or lactambridges formed by glutamic and aspartic acid residues linking ornithineand, respectively, lysine residues, or by glutamic acid residues linking2,4-diaminobutyric acid residues located at opposite β-strand positionsby amide bond formation. The formation of such interstrand linkages canbe effected by methods well known in the art.

For the formation of disulfide bridges preferably a solution of 10equivalents of iodine solution is applied in DMF or in a mixture ofCH₂Cl₂/MeOH for 1.5 h which is repeated for another 3 h with a freshiodine solution after filtering of the iodine solution, or in a mixtureof DMSO and acetic acid solution, buffered with 5% with NaHCO₃ to pH 5-6for 4 h, or in water after having been adjusted to pH 8 with ammoniumhydroxide solution by stirring for 24 h or ammonium acetate bufferadjusted to pH 8 in the presence of air, or in a solution of NMP andtri-n-butylphosphine (preferably 50 eq.).

Detachment of the fully protected linear peptide from the solid supportis achieved by immersion of the reaction tubes, in combination with theholder block and manifold, in reaction wells containing a solution ofthe cleavage reagent (preferably 3 to 5 ml). Gas flow, temperaturecontrol, agitation and reaction monitoring are implemented as describedabove and as desired to effect the detachment reaction. The reactiontubes, in combination with the holder block and manifold, aredisassembled from the reservoir block and raised above the solutionlevel but below the upper lip of the reaction wells, and gas pressure isapplied through the manifold inlet (while closing the outlet) toefficiently expel the final product solution into the reservoir wells.The resin remaining in the reaction tubes is then washed 2 to 5 times asabove with 3 to 5 ml of an appropriate solvent to extract (wash out) asmuch of the detached product as possible. The product solutions thusobtained are combined, taking care to avoid cross-mixing. The individualsolutions/extracts are then manipulated as needed to isolate the finalcompounds. Typical manipulations include, but are not limited to,evaporation, concentration, liquid/liquid extraction, acidification,basification, neutralization or additional reactions in solution.

The solutions containing fully protected linear peptide derivativeswhich have been cleaved off from the solid support and neutralized witha base, are evaporated. Cyclization is then effected in solution usingsolvents such as DCM, DMF, dioxane, THF and the like. Various couplingreagents which were mentioned earlier can be used for the cyclization.The duration of the cyclization is about 6-48 hours, preferably about 16hours. The progress of the reaction is followed, e.g. by RP-HPLC(Reverse Phase High Performance Liquid Chromatography). Then the solventis removed by evaporation, the fully protected cyclic peptide derivativeis dissolved in a solvent which is not miscible with water, such as DCM,and the solution is extracted with water or a mixture of water-misciblesolvents, in order to remove any excess of the coupling reagent.

Finally, the fully protected peptide derivative is treated with 95% TFA,2.5% H₂O, 2.5% TIS or another combination of scavengers for effectingthe cleavage of protecting groups. The cleavage reaction time iscommonly 30 minutes to 12 hours, preferably about 2.5 hours. Thevolatiles are evaporated to dryness and the crude peptide is dissolvedin 20% AcOH in water and extracted with isopropyl ether or othersolvents which are suitable therefor. The aqueous layer is collected andevaporated to dryness, and the fully deprotected cyclic peptidederivative of formula I is obtained as end-product. Depending on itspurity, this peptide derivative can be used directly for biologicalassays, or it has to be further purified, for example by preparativeHPLC.

Alternatively the detachment, cyclisation and complete deprotection ofthe fully protected peptide from the solid support can be achievedmanually in glass vessels.

As mentioned earlier, it is thereafter possible, if desired, to converta fully deprotected product of formula I thus obtained into apharmaceutically acceptable salt or to convert a pharmaceuticallyacceptable, or unacceptable, salt thus obtained into the correspondingfree compound of formula I or into a different, pharmaceuticallyacceptable, salt. Any of these operations can be carried out by methodswell known in the art.

The template starting materials of formula II used in the processes ofthe invention, pre-starting materials therefor, and the preparation ofthese starting and pre-starting materials are described in InternationalApplication PCT/EP02/01711, published as WO 02/070547 A1.

The β-hairpin peptidomimetics of the invention can be used in a widerange of applications in order to inhibit the growth of or to killmicroorganisms. In particular they can be used to selectively inhibitthe growth of or to kill microorganisms such as Pseudomonas aeruginosa.

They can be used for example as disinfectants or as preservatives formaterials such as foodstuffs, cosmetics, medicaments and othernutrient-containing materials. The β-hairpin peptidomimetics of theinvention can also be used to treat or prevent diseases related tomicrobial infection in plants and animals.

For use as disinfectants or preservatives the β-hairpin peptidomimeticscan be added to the desired material singly, as mixtures of severalβ-hairpin peptidomimetics or in combination with other antimicrobialagents. The β-hairpin peptidomimetics may be administered per se or maybe applied as an appropriate formulation together with carriers,diluents or excipients well known in the art.

When used to treat or prevent infections or diseases related to suchinfections, particularly infections related to respiratory diseases suchas cystic fibrosis, emphysema and asthma; infections related to skin orsoft tissue diseases such as surgical wounds, traumatic wounds and burnwounds; infections related to gastrointestinal diseases such as epidemicdiarrhea, necrotizing enterocolitis and typhlitis; infections related toeye diseases such as keratitis and endophthalmitis; infections relatedto ear diseases such as otitis, infections related to CNS diseases suchas brain abscess and meningitis; infections related to bone diseasessuch as osteochondritis and osteomyelitis; infections related tocardiovascular diseases such as endocartitis and pericarditis; orinfections related to gastrourinal diseases such as epididymitis,prostatitis and urethritis; the β-hairpin peptidomimetics can beadministered singly, as mixtures of several β-hairpin peptidomimetics,in combination with other antimicrobial or antibiotic agents, or anticancer agents, or antiviral (e.g. anti-HIV) agents, or in combinationwith other pharmaceutically active agents. The β-hairpin peptidomimeticscan be administered per se or as pharmaceutical compositions.

Pharmaceutical compositions comprising β-hairpin peptidomimetics of theinvention may be manufactured by means of conventional mixing,dissolving, granulating, coated tablet-making, levigating, emulsifying,encapsulating, entrapping or lyophilizing processes. Pharmaceuticalcompositions may be formulated in conventional manner using one or morephysiologically acceptable carriers, diluents, excipients or auxiliarieswhich facilitate processing of the active β-hairpin peptidomimetics intopreparations which can be used pharmaceutically. Proper formulationdepends upon the method of administration chosen.

For topical administration the β-hairpin peptidomimetics of theinvention may be formulated as solutions, gels, ointments, creams,suspensions, etc. as are well-known in the art.

Systemic formulations include those designed for administration byinjection, e.g. subcutaneous, intravenous, intramuscular, intrathecal orintraperitoneal injection, as well as those designed for transdermal,transmucosal, oral or pulmonary administration.

For injections, the β-hairpin peptidomimetics of the invention may beformulated in adequate solutions, preferably in physiologicallycompatible buffers such as Hink's solution, Ringer's solution, orphysiological saline buffer. The solution may contain formulatory agentssuch as suspending, stabilizing and/or dispersing agents. Alternatively,the β-hairpin peptidomimetics of the invention may be in powder form forcombination with a suitable vehicle, e.g., sterile pyrogen-free water,before use. For transmucosal administration, penetrants appropriate tothe barrier to be permeated are used in the formulation as known in theart.

For oral administration, the compounds can be readily formulated bycombining the active β-hairpin peptidomimetics of the invention withpharmaceutically acceptable carriers well known in the art. Suchcarriers enable the β-hairpin peptidomimetics of the invention to beformulated as tablets, pills, dragees, capsules, liquids, gels, syrups,slurries, suspensions etc., for oral ingestion of a patient to betreated. For oral formulations such as, for example, powders, capsulesand tablets, suitable excipients include fillers such as sugars, such aslactose, sucrose, mannitol and sorbitol; cellulose preparations such asmaize starch, wheat starch, rice starch, potato starch, gelatin, gumtragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodiumcarboxymethylcellulose, and/or polyvinylpyrrolidone (PVP); granulatingagents; and binding agents. If desired, desintegrating agents may beadded, such as cross-linked polyvinylpyrrolidones, agar, or alginic acidor a salt thereof, such as sodium alginate. If desired, solid dosageforms may be sugar-coated or enteric-coated using standard techniques.

For oral liquid preparations such as, for example, suspensions, elixirsand solutions, suitable carriers, excipients or diluents include water,glycols, oils, alcohols, etc. In addition, flavoring agents,preservatives, coloring agents and the like may be added.

For buccal administration, the composition may take the form of tablets,lozenges, etc. formulated as usual.

For administration by inhalation, the β-hairpin peptidomimetics of theinvention are conveniently delivered in form of an aeorosol spray frompressurized packs or a nebulizer, with the use of a suitable propellant,e.g. dichlorodifluoromethane, trichlorofluromethane, carbon dioxide oranother suitable gas. In the case of a pressurized aerosol the dose unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of e.g. gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the β-hairpinpeptidomimetics of the invention and a suitable powder base such aslactose or starch.

The compounds may also be formulated in rectal or vaginal compositionssuch as suppositories together with appropriate suppository bases suchas cocoa butter or other glycerides.

In addition to the formulations described previously, the β-hairpinpeptidomimetics of the invention may also be formulated as depotpreparations. Such long acting formulations may be administered byimplantation (e.g. subcutaneously or intramuscularly) or byintramuscular injection. For the manufacture of such depot preparationsthe β-hairpin peptidomimetics of the invention may be formulated withsuitable polymeric or hydrophobic materials (e.g. as an emulsion in anacceptable oil) or ion exchange resins, or as sparingly soluble salts.

In addition, other pharmaceutical delivery systems may be employed suchas liposomes and emulsions well known in the art. Certain organicsolvents such as dimethylsulfoxide also may be employed. Additionally,the β-hairpin peptidomimetics of the invention may be delivered using asustained-release system, such as semipermeable matrices of solidpolymers containing the therapeutic agent. Various sustained-releasematerials have been established and are well known by those skilled inthe art. Sustained-release capsules may, depending on their chemicalnature, release the compounds for a few weeks up to over 100 days.Depending on the chemical nature and the biological stability of thetherapeutic agent, additional strategies for protein stabilization maybe employed.

As the β-hairpin pepdidomimetics of the invention may contain chargedresidues, they may be included in any of the above-describedformulations as such or as pharmaceutically acceptable salts.Pharmaceutically acceptable salts tend to be more soluble in aqueous andother protic solvents than are the corresponding free base forms.

The β-hairpin peptidomimetics of the invention, or compositions thereof,will generally be used in an amount effective to achieve the intendedpurpose. It is to be understood that the amount used will depend on aparticular application.

For example, for use as a desinfectant or preservative, anantimicrobially effective amount of a β-hairpin peptidomimetic of theinvention, or a composition thereof, is applied or added to the materialto be desinfected or preserved. By antimicrobially effective amount ismeant an amount of a β-hairpin peptidomimetic of the invention, or acomposition thereof, that inhibits the growth of, or is lethal to, atarget microbe population. While the antimicrobially effective amountwill depend on a particular application, for use as desinfectants orpreservatives the β-hairpin peptidomimetics of the invention, orcompositions thereof, are usually added or applied to the material to bedesinfected or preserved in relatively low amounts. Typically, theβ-hairpin peptidomimetics of the invention comprise less than about 5%by weight of a desinfectant solution or material to be preserved,preferably less than 1% by weight and more preferably less than 0.1% byweight. An ordinary skilled expert will be able to determineantimicrobially effective amounts of particular β-hairpinpepdidomimetics of the invention for particular applications withoutundue experimentation using, for example, the in vitro assays providedin the examples.

For use to treat or prevent microbial infections or diseases related tosuch infections, the β-hairpin pepidomimetics of the invention, orcompositions thereof, are administered or applied in a therapeuticallyeffective amount. By therapeutically effective amount is meant an amounteffective in ameliorating the symptoms of, or in ameliorating, treatingor preventing microbial infections or diseases related thereto.Determination of a therapeutically effective amount is well within thecapacities of those skilled in the art, especially in view of thedetailed disclosure provided herein.

As in the case of desinfectants and preservatives, for topicaladministration to treat or prevent bacterial infections atherapeutically effective dose can be determined using, for example, thein vitro assays provided in the examples. The treatment may be appliedwhile the infection is visible, or even when it is not visible. Anordinary skilled expert will be able to determine therapeuticallyeffective amounts to treat topical infections without undueexperimentation.

For systemic administration, a therapeutically effective dose can beestimated initially from in vitro assays. For example, a dose can beformulated in animal models to achieve a circulating β-hairpinpeptidomimetic concentration range that includes the IC₅₀ as determinedin the cell culture (i.e. the concentration of a test compound that islethal to 50% of a cell culture), the MIC, as determined in cell culture(i.e. the concentration of a test compound that is lethal to 100% of acell culture). Such information can be used to more accurately determineuseful doses in humans.

Initial dosages can also be determined from in vivo data, e.g. animalmodels, using techniques that are well known in the art. One havingordinary skills in the art could readily optimize administration tohumans based on animal data.

Dosage amount for applications as antimicrobial agents may be adjustedindividually to provide plasma levels of the β-hairpin peptidomimeticsof the invention which are sufficient to maintain the therapeuticeffect. Therapeutically effective serum levels may be achieved byadministering multiple doses each day.

In cases of local administration or selective uptake, the effectivelocal concentration of the β-hairpin peptidomimetics of the inventionmay not be related to plasma concentration. One having the skills in theart will be able to optimize therapeutically effective local dosageswithout undue experimentation.

The amount of β-hairpin peptidomimetics administered will, of course, bedependent on the subject being treated, on the subject's weight, theseverity of the affliction, the manner of administration and thejudgement of the prescribing physician.

The antimicrobial therapy may be repeated intermittently whileinfections are detectable or even when they are not detectable. Thetherapy may be provided alone or in combination with other drugs, suchas for example antibiotics or other antimicrobial agents.

Normally, a therapeutically effective dose of the β-hairpinpeptidomimetics described herein will provide therapeutic benefitwithout causing substantial toxicity.

Hemolysis of red blood cells is often employed for assessment oftoxicity of related compounds such as protegrin or tachyplesin. Valuesare given as %-lysis of red blood cells observed at a concentration of100 μg/ml. Typical values determined for cationic peptides such asprotegrin and tachyplesin range between 30-40% with average MIC-valuesof 1-5 □μg/ml over a wide range of pathogens. Normally, β-hairpinpeptidomimetics of the invention will show hemolysis in a range of0.5-10%, often in a range of 1-5%, at activity levels comparable tothose mentioned above for protegrin and tachyplesin. Thus preferredcompounds exhibit low MIC-values and low %-hemolysis of red blood cellsobserved at a concentration of 100 μg/ml.

Toxicity of the β-hairpin peptidomimetics of the invention herein can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, e.g., by determining the LD₅₀ (the dose lethal to50% of the population) or the LD₁₀₀ (the dose lethal to 100% of thepopulation). The dose ratio between toxic and therapeutic effect is thetherapeutic index. Compounds which exhibit high therapeutic indices arepreferred. The data obtained from these cell culture assays and animalstudies can be used in formulating a dosage range that is not toxic foruse in humans. The dosage of the β-hairpin peptidomimetics of theinvention lies preferably within a range of circulating concentrationsthat include the effective dose with little or no toxicity. The dosagemay vary within the range depending upon the dosage form employed andthe route of administration utilized. The exact formulation, route ofadministration and dose can be chosen by the individual physician inview of the patient's condition (see, e.g. Fingl et al. 1975, In: ThePharmacological Basis of Therapeutics, Ch. 1, p. 1).

The following Examples illustrate the invention in more detail but arenot intended to limit its scope in any way. The following abbreviationsare used in these Examples:

-   -   HBTU: 1-benzotriazol-1-yl-tetramethylurounium        hexafluorophosphate (Knorr et al. Tetrahedron Lett. 1989, 30,        1927-1930);    -   HCTU: 1-Benzotriazol        1-[bis(dimethylamino)methylene]-5chloro-hexafluorophosphate-1,3-oxide    -   HOBt: 1-hydroxybenzotriazole;    -   DMA: diisopropylethylamine;    -   HOAT: 7-aza-1-hydroxybenzotriazole;    -   HATU: O-(7-aza-benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronoium        hexafluorophosphate (Carpino et al. Tetrahedron Lett. 1994, 35,        2279-2281).

EXAMPLES 1. Peptide Synthesis Coupling of the First Protected Amino AcidResidue to the Resin

0.5 g of 2-chlorotritylchloride resin (Barlos et al. Tetrahedron Lett.1989, 30, 3943-3946) (0.83 mMol/g, 0.415 mmol) was filled into a driedflask. The resin was suspended in CH₂Cl₂ (2.5 ml) and allowed to swellat room temperature under constant stirring for 30 min. The resin wastreated with 0.415 mMol (1 eq) of the first suitably protected aminoacid residue (see below) and 284 μl (4 eq) of diisopropylethylamine(DIEA) in CH₂Cl₂ (2.5 ml), the mixture was shaken at 25° C. for 4 hours.The resin was shaken (CH₂Cl₂/MeOH/DIEA: 17/2/1), 30 ml for 30 min; thenwashed in the following order with CH₂Cl₂ (1×), DMF (1×), CH₂Cl₂ (1×),MeOH (1×), CH₂Cl₂(1×), MeOH (1×), CH₂Cl₂ (2×), Et₂O (2×) and dried undervacuum for 6 hours.

Loading was typically 0.6-0.7 mMol/g.

The following preloaded resin was prepared:Fmoc-Pro-2-chlorotritylresin.

Synthesis of the Fully Protected Peptide Fragment

The synthesis was carried out using a Syro-peptide synthesizer(Multisyntech) using 24 to 96 reaction vessels. In each vessel wereplaced 60 mg (weight of the resin before loading) of the above resin.The following reaction cycles were programmed and carried out:

Step Reagent Time 1 CH₂Cl₂, wash and swell (manual) 3 × 1 min. 2 DMF,wash and swell 1 × 5 min 3 40% piperidine/DMF 2 × 5 min. 4 DMF, wash 5 ×2 min. 5 5 equiv. Fmoc amino acid/DMF + 2 × 60 min. 5 eq. HCTU + 5 eq.DIEA 6 DMF, wash 4 × 2 min. 7 CH₂Cl₂, wash (at the end of the 3 × 2 min.synthesis)

Steps 3 to 6 are repeated to add each amino-acid.

After the synthesis of the fully protected peptide fragment had beenterminated, then subsequently the cleavage, cyclization and work upprocedure as described hereinbelow, was used for the preparation of thepeptides.

Analytical Methods:

Method 1: Analytical HPLC retention times (RT, in minutes) weredetermined using an Jupiter Proteo column (90A, 150×2.0 mm, cod.00F4396-B0—Phenomenex) with the following solvents A (H₂O+0.1% TFA) andB (CH₃CN+0.1% TFA) and the gradient: 0 min: 95% A, 5% B; 20 min: 40% A60% B; 21-23 min: 0% A, 100% B; 23.1-30 min: 95% A, 5% B.

Method 2: Analytical HPLC retention times (RT, in minutes) weredetermined using an Aquity UPLC BEH C18 column (1.7 μm, 100×2.1 mm, cod.186002352—Waters) with the following solvents A (H₂O+0.1% TFA) and B(CH₃CN+0.085% TFA) and the gradient: 0 min: 95% A, 5% B; 0.2 min: 95% A5% B; 4 min: 35% A, 65% B; 4.2 min: 5% A, 95% B; 4.25 min: 95% A, 5% B;4.9 min: 95% A, 5% B.

Procedure: Cleavage, Cyclization and Work Up of Backbone CyclizedPeptides Cleavage, Backbone Cyclization and Purification of the Peptide

After assembly of linear peptides, the resin was suspended in 1 ml (0.39mMol) of 1% TFA in CH₂Cl₂ (v/v) for 3 minutes and filtered, and thefiltrate was neutralized with 1 ml (1.17 mMol, 3 eq.) of 20% DIEA inCH₂Cl₂ (v/v). This procedure was repeated twice to ensure completion ofthe cleavage. The resin was washed with 2 ml of CH₂Cl₂. The CH₂Cl₂ layerwas evaporated to dryness.

The fully protected linear peptide was solubilised in 8 ml of dry DMF.Then 2 eq. of HATU in dry DMF (1 ml) and 4 eq. of DIPEA in dry DMF (1ml) were added to the peptide, followed by stirring for 16 h. Thevolatiles were evaporated to dryness. The crude cyclic peptide wasdissolved in 7 ml of CH₂Cl₂ and extracted with 10% acetonitrile in water(4.5 ml) three times. The CH₂Cl₂ layer was evaporated to dryness. Tofully deprotect the peptide, 3 ml of cleavage cocktail TFA:TIS:H₂O(95:2.5:2.5) were added, and the mixture was stirred for 2.5 h. Thevolatile was evaporated to dryness and the crude peptide was dissolvedin 20% AcOH in water (7 ml) and extracted with diisopropyl ether (4 ml)for three times. The aqueous layer was collected and evaporated todryness, and the residue was purified by preparative reverse phaseLC-MS.

After lyophilisation the products were obtained as white powders andanalysed by HPLC-ESI-MS analytical methods as described above. Theanalytical data comprising purity after preparative HPLC and ESI-MS areshown in Table 1.

Examples 1-50, are shown in Table 1. The peptides were synthesizedstarting with the amino acid L-Pro which was grafted to the resin.Starting resin was Fmoc-Pro-2-chlorotrityl resin, which was prepared asdescribed above. The linear peptides were synthesized on solid supportaccording to the procedure described above in the following sequence:Resin-Pro-^(D)Pro-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Ex. 1-50, werecleaved from the resin, cyclized, deprotected and purified as indicatedby preparative reverse phase LC-MS.

After lyophilisation the products were obtained as white powders andanalysed by HPLC-ESI-MS methods as described above.

HPLC-retention times (minutes) were determined using the analyticalmethods as described above. Examples 1 to 39 were analysed with method1, for Examples 40-50 method 2 was used:

Ex. 1 (8.87), Ex. 2 (9.26), Ex. 3 (9.34), Ex. 4 (9.45), Ex. 5 (9.48),Ex. 6 (9.44), Ex. 7 (10.11), Ex. 8 (9.99), Ex. 9 (10.22), Ex. 10 (9.76),Ex. 11 (10.56), Ex. 12 (11.37), Ex. 13 (9.13), Ex. 14 (9.34), Ex. 15(8.80), Ex. 16 (9.23); Ex. 17 (9.65), Ex. 18 (9.18), Ex. 19 (8.37), Ex.20 (8.86), Ex. 21 (8.78), Ex. 22 (9.32), Ex. 23 (9.58), Ex. 24 (9.27),Ex. 25 (9.31), Ex. 26 (9.24), Ex. 27 (9.23), Ex. 28 (9.34), Ex. 29(9.66), Ex. 30 (9.88), Ex. 31 (9.62), Ex. 32(8.86), Ex. 33 (9.73), Ex.34 (10.46), Ex. 35 (9.21), Ex. 36 (9.80), Ex. 37 (9.73), Ex. 38 (9.20),Ex. 39 (9.53), Ex. 40 (2.07), Ex. 41 (1.77), Ex. 42 (1.66), Ex. 43(1.67), Ex. 44 (1.81), Ex. 45 (1.87), Ex. 46 (1.81), Ex. 47 (1.83), Ex.48 (1.79), Ex. 49 (1.88), Ex. 50 (2.17).

TABLE 1 Examples Purity [M + Example Sequ. ID P1 P2 P3 P4 P5 P6 P7 P8 P9P10 P11 P12 Template %^(a)) 2H]/2 1 SEQ ID NO: 1 Thr Trp Ile Dab Lys DabDab Trp Dab Dab Ala Dab ^(D)Pro^(L)Pro 95 790.9 2 SEQ ID NO: 2 Thr TrpIle Dab Lys Dab Dab Trp Dab Dab Gly Dab ^(D)Pro^(L)Pro 95 783.9 3 SEQ IDNO 3 Thr Trp Ile Dab Lys Dab Dab Trp Dab Dab ^(D)Ala Dab ^(D)Pro^(L)Pro95 791.1 4 SEQ ID NO 4 Thr Trp Ile Dab Lys Dab Dab Trp Dab Dab ^(D)ValDab ^(D)Pro^(L)Pro 95 805.2 5 SEQ ID NO: 5 Thr Trp Ile Dab Lys Dab DabTrp Dab Dab Aib Dab ^(D)Pro^(L)Pro 86 798.0 6 SEQ ID NO: 6 Thr Trp IleDab Lys Dab Dab Trp Dab Dab Abu Dab ^(D)Pro^(L)Pro 86 797.9 7 SEQ ID NO:7 Thr Trp Ile Dab Lys Dab Dab Trp Dab Dab Leu Dab ^(D)Pro^(L)Pro 95812.5 8 SEQ ID NO: 8 Thr Trp Ile Dab Lys Dab Dab Trp Dab Dab Ile Dab^(D)Pro^(L)Pro 89 812.6 9 SEQ ID NO: 9 Thr Trp Ile Dab Lys Dab Dab TrpDab Dab Nle Dab ^(D)Pro^(L)Pro 39 812.3 10 SEQ ID NO: 10 Thr Trp Ile DabLys Dab Dab Trp Dab Dab Nva Dab ^(D)Pro^(L)Pro 87 805.1 11 SEQ ID NO: 11Thr Trp Ile Dab Lys Dab Dab Trp Dab Dab Chg Dab ^(D)Pro^(L)Pro 82 825.712 SEQ ID NO: 12 Thr Trp Ile Dab Lys Dab Dab Trp Dab Dab Cha Dab^(D)Pro^(L)Pro 95 831.9 13 SEQ ID NO: 13 Thr Trp Ile Dab Lys Dab Dab TrpDab Dab Gln Dab ^(D)Pro^(L)Pro 87 819.6 14 SEQ ID NO: 14 Thr Trp Ile DabLys Dab Dab Trp Dab Dab Asp Dab ^(D)Pro^(L)Pro 80 813.5 15 SEQ ID NO: 15Thr Trp Ile Dab Lys Dab Dab Trp Dab Dab Glu Dab ^(D)Pro^(L)Pro 83 820.116 SEQ ID NO: 16 Thr Trp Ile Dab Lys Dab Dab Trp Dab Dab Thr Dab^(D)Pro^(L)Pro 95 806.1 17 SEQ ID NO: 17 Thr Trp Ile Dab Lys Dab Dab TrpDab Dab Pro Dab ^(D)Pro^(L)Pro 85 804.0 18 SEQ ID NO: 18 Cit Trp Ile DabLys Dab Dab Trp Dab Dab Ala Dab ^(D)Pro^(L)Pro 95 819.6 19 SEQ ID NO: 19Thr Tyr Ile Dab Lys Dab Dab Trp Dab Dab Ala Dab ^(D)Pro^(L)Pro 95 779.920 SEQ ID NO: 20 Thr Trp Ile Dab Lys Dab Dab Tyr Dab Dab Ala Dab^(D)Pro^(L)Pro 95 779.5 21 SEQ ID NO: 21 Thr Trp Ile Dab Lys Dab His TrpDab Dab Ala Dab ^(D)Pro^(L)Pro 95 810.0 22 SEQ ID NO: 22 Ala Trp Ile DabLys Dab Dab Trp Dab Dab Ala Dab ^(D)Pro^(L)Pro 95 776.2 23 SEQ ID NO: 23Ala Trp Ile Dab Dab Dab Dab Trp Dab Dab Val Dab ^(D)Pro^(L)Pro 95 776.424 SEQ ID NO: 24 Thr Trp Ile Lys Lys Dab Dab Trp Dab Dab Ala Dab^(D)Pro^(L)Pro 87 805.1 25 SEQ ID NO: 25 Thr Trp Ile Dab Lys Lys Dab TrpDab Dab Ala Dab ^(D)Pro^(L)Pro 95 805.0 26 SEQ ID NO: 26 Thr Trp Ile DabLys Dab Lys Trp Dab Dab Ala Dab ^(D)Pro^(L)Pro 87 805.2 27 SEQ ID NO: 27Thr Trp Ile Dab Lys Dab Dab Trp Lys Dab Ala Dab ^(D)Pro^(L)Pro 95 805.128 SEQ ID NO: 28 Thr Trp Ile Dab Lys Dab Dab Trp Dab Dab Ala Lys^(D)Pro^(L)Pro 95 805.0 29 SEQ ID NO: 29 Thr Trp Ile Gln Lys Dab Dab TrpDab Dab Ala Dab ^(D)Pro^(L)Pro 86 805.2 30 SEQ ID NO: 30 Thr Trp Ile GlnLys Dab Dab Trp Dab Dab Val Dab ^(D)Pro^(L)Pro 88 819.1 31 SEQ ID NO: 31Thr Trp Nle Dab Lys Dab Dab Trp Dab Dab Ala Dab ^(D)Pro^(L)Pro 95 791.132 SEQ ID NO: 32 Thr Trp Val Dab Lys Dab Dab Trp Dab Dab Ala Dab^(D)Pro^(L)Pro 95 784.0 33 SEQ ID NO: 33 Thr Trp Chg Dab Lys Dab Dab TrpDab Dab Ala Dab ^(D)Pro^(L)Pro 95 804.4 34 SEQ ID NO: 34 Thr Trp Cha DabLys Dab Dab Trp Dab Dab Ala Dab ^(D)Pro^(L)Pro 95 811.5 35 SEQ ID NO: 35Thr Trp Ile Dab Lys Dab Dab Trp Dab Dab Hse Dab ^(D)Pro^(L)Pro 95 806.436 SEQ ID NO: 36 Thr Trp Ile Dab Lys Dab Dab Trp Dab Dab t-BuG Dab^(D)Pro^(L)Pro 95 812.5 37 SEQ ID NO: 37 Thr Trp Ile Dab Lys Dab Dab TrpDab Dab Cpa Dab ^(D)Pro^(L)Pro 89 811.3 38 SEQ ID NO: 38 Thr Trp Ile DabLys Dab Dab Trp Dab Dab Asn Dab ^(D)Pro^(L)Pro 95 813.1 39 SEQ ID NO: 39Thr Trp Ile Dab Lys Dab Gln Trp Dab Dab Ala Dab ^(D)Pro^(L)Pro 95 805.240 SEQ ID NO: 40 Thr Trp Ile Gln Lys Dab Dab Trp Dab Dab Ala Gln^(D)Pro^(L)Pro 95 819.6 41 SEQ ID NO: 41 Thr Trp Ile Dab Lys ^(D)Dab DabTrp Dab Dab Ala Dab ^(D)Pro^(L)Pro 91 791.2 42 SEQ ID NO: 42 Asp Tyr IleDab Lys ^(D)Dab Dab Trp Dab Dab Ala Dab ^(D)Pro^(L)Pro 85 786.6 43 SEQID NO: 43 Asp Tyr Ile Dab Orn ^(D)Dab Dab Trp Dab Dab Ala Dab^(D)Pro^(L)Pro 85 779.6 44 SEQ ID NO: 44 Glu Trp Ile Dab Lys ^(D)Dab DabTrp Dab Dab Ala Dab ^(D)Pro^(L)Pro 78 805.1 45 SEQ ID NO: 45 Glu Trp IleDab Lys ^(D)Dab Dab Trp Dab Dab Ala Gln ^(D)Pro^(L)Pro 82 819.2 46 SEQID NO: 46 Glu Trp Ile Dab Lys ^(D)Dab Dab Trp Dab Dab Ala Dap^(D)Pro^(L)Pro 83 798.0 47 SEQ ID NO: 47 Glu Trp Ile Dab Orn ^(D)Dab DabTrp Dab Dab Ala Dab ^(D)Pro^(L)Pro 85 798.3 48 SEQ ID NO: 48 Thr Trp IleDab Orn ^(D)Dab Dab Trp Dab Dab Ala Dab ^(D)Pro^(L)Pro 86 784.1 49 SEQID NO: 49 Thr Trp Ile Dab Orn ^(D)Dab Dab Trp Dab Dab Ala Ser^(D)Pro^(L)Pro 91 777.7 50 SEQ ID NO: 50 Glu Trp Ile Gln Lys Dab Dab SerDab Dab Ala Ser ^(D)Pro^(L)Pro 95 805.8 ^(a))%-puritity of compoundsafter prep. HPLC.

2. Biological Methods 2.1. Preparation of the Peptide Samples.

Lyophilized peptides were weighed on a Microbalance (Mettler MT5) anddissolved in sterile water to a final concentration of 1 mg/ml unlessstated otherwise. Stock solutions were kept at +4° C., light protected.

2.2. Antimicrobial Activity of the Peptides.

The selective antimicrobial activities of the peptides were determinedin 96-well plates (Nunclon polystyrene) by the standard NCCLS brothmicrodilution method (see ref 1, below) with slight modifications.Innocula of the microorganisms were diluted into Mueller-Hinton (MH)broth+0.02% BSA and compared with a 0.5 Mcfarland standard to give appr.10⁶ colony forming units (CFU)/ml. Aliquots (50 μl) of inoculate wereadded to 50 μl of MH broth+0.02% BSA containing the peptide in serialtwo-fold dilutions. The following microorganisms were used to determineantibiotic selectivity of the peptides: Escherichia coli (ATCC 25922),Pseudomonas aeruginosa (P. aeruginosa ATCC 27853, P8191900, P1021903,P1021913, IMP 1 Livermore 3140). Antimicrobial activities of thepeptides were expressed as the minimal inhibitory concentration (MIC) inμg/ml at which no visible growth was observed after 18-20 hours ofincubation at 37° C.

2.3. Cytotoxicity Assay

The cytotoxicity of the peptides to HELA cells (Acc57) and COS-7 cells(CRL-1651) was determined using the MTT reduction assay [see ref 2 and3, below]. Briefly the method was as follows: HELA cells and COS-7 cellswere seeded at 7.0×10³ and, respectively, 4.5×10³ cells per well andgrown in 96-well microtiter plates for 24 hours at 37° C. at 5% CO₂. Atthis point, time zero (Tz) was determined by MTT reduction (see below).The supernatant of the remaining wells was discarded, and fresh mediumand the peptides in serial dilutions of 12.5, 25 and 50 μM weredispensed into the wells. Each peptide concentration was assayed intriplicate. Incubation of the cells was continued for 48 hours at 37° C.at 5% CO₂. Wells were then washed once with phosphate buffered saline(PBS) and subsequently 100 μl MTT reagent (0.5 mg/ml in medium RPMI1640and, respectively, DMEM) were added to the wells. This was incubated at37° C. for 2 hours and subsequently the medium was aspirated and 100 μlisopropanol were added to each well. The absorbance at 595 nm of thesolubilized product was measured (OD₅₉₅ peptide). For each concentrationaverages were calculated from triplicates. The percentage of growth wascalculated as follows: (OD₅₉₅peptide-OD₅₉₅Tz-OD₅₉₅Emptywell)/(OD₅₉₅Tz-OD₅₉₅Empty well)×100% and was plotted for each peptideconcentration.

The LC 50 values (Lethal Concentration, defined as the concentrationthat kills 50% of the cells) were determined for each peptide by usingthe trend line function of EXCEL (Microsoft Office 2000) for theconcentrations (50, 25, 12.5 and 0 μM), the corresponding growthpercentages and the value −50, (=TREND(C50:C0,%50:%0,−50)). The GI 50(Growth Inhibition) concentrations were calculated for each peptide byusing a trend line function for the concentrations (50, 25, 12.5 and 0μg/ml), the corresponding percentages and the value 50, (=TREND(C₅₀:C₀,%₅₀:%₀,50).

2.4. Hemolysis

The peptides were tested for their hemolytic activity against human redblood cells (hRBC). Fresh hRBC were washed three times with phosphatebuffered saline (PBS) by centrifugation for 10 min at 2000×g. Peptidesat a concentration of 100 μM were incubated with 20% v/v hRBC for 1 hourat 37° C. The final erythrocyte concentration was approximately 0.9×10⁹cells per ml. A value of 0% and, respectively, 100% cell lysis wasdetermined by incubation of the hRBC in the presence of PBS alone and,respectively, 0.1% Triton X-100 in H₂O. The samples were centrifuged,the supernatant was 20-fold diluted in PBS buffer and the opticaldensity (OD) of the sample at 540 nM was measured. The 100% lysis value(OD₅₄₀H₂O) gave an OD₅₄₀ of approximately 1.3-1.8. Percent hemolysis wascalculated as follows: (OD₅₄₀peptide/OD₅₄₀H₂O)×100%.

2.5. Plasma Stability

405 μl of plasma/albumin solution were placed in a polypropylene (PP)tube and spiked with 45 μl of compound from a 100 mM solution B, derivedfrom 135 μl of PBS and 15 μl of 1 mM peptide in PBS, pH 7.4. 150 μlaliquots were transferred into individual wells of the 10 kDa filterplate (Millipore MAPPB 1010 Biomax membrane). For “0 minutes controls”:270 μl of PBS were placed in a PP tube and 30 μl of stock solution B wasadded and mixed. 150 μl of control solution were placed into one well ofthe filter plate and served as “filtered control”.

Further 150 μl of control solution were placed directly into a receiverwell (reserved for filtrate) and served as “not-filtered control”. Theentire plate including evaporation lid was incubated for 60 min at 37°C. Plasma samples (rat plasma: Harlan Sera lab UK, human plasma:Blutspendezentrum Zürich) were centrifuged at least for 2 h at 4300 rpm(3500 g) and 15° C. in order to yield 100 μl filtrate. For “serumalbumin”-samples (freshly prepared human albumin: Sigma A-4327, ratalbumin: Sigma A-6272, all at 40 mg/ml concentration in PBS)approximately 1 hour of centrifugation was sufficient. The filtrates inthe receiver PP plate were analysed by LC/MS as follows: Column: JupiterC18 (Phenomenex), mobile phases: (A) 0.1% formic acid in water and (B)acetonitrile, gradient: 5%-100% (B) in 2 minutes, electrosprayionization, MRM detection (triple quadrupole). The peak areas weredetermined and triplicate values were averaged. The binding wasexpressed in percent of the (filtered and not-filtered time point 0 min)control 1 and 2 by: 100−(100×T₆₀/T₀). The average from these values wasthen calculated.

2.6. Pharmacokinetic Study (PK)

Pharmacokinetic Study after Single Intravenous, Subcutaneous andIntraperitoneal Administration in Mice

Pharmacokinetic study after single intravenous (i.v.) and subcutaneous(s.c.) administration was performed for the compound of Example 1 (“Ex.1”). CD-1 mice (20-25 g) were used in the study. Physiological salinewas used a vehicle. The volume was 2 ml/kg i.v., and 5 ml/kg s.c. andthe peptide Ex. 1 was injected to give a final intravenous dose of 1mg/kg, and a subcutaneous dose of 5 mg/kg. Approximately 200-250 μl ofblood was removed under light isoflurane anesthesia by cardiac punctureat predetermined time intervals (0, 5, 15, 30 min and 1, 2, 3, 4 and 5hours for the i.v. study and 0, 15, 30 min and 1, 2, 4, 6, 8 and 10hours for the s.c. study) and added to heparinized tubes. Plasma wasremoved from pelleted cells upon centrifugation and frozen at −80° C.prior to HPLC-MS analysis.

Preparation of the Plasma Calibration Samples

“Blank” mouse plasma from untreated animals was used. Aliquots of plasmaof 0.2 ml each were spiked with 50 ng of propranolol (Internal Standard,IS), (sample preparation by solid phase extraction on OASIS® HLBcartridges (Waters)) and with known amounts of Ex. 1 in order to obtain9 plasma calibration samples in the range 10-5000 nM. The OASIS® HLBcartridges were conditioned with 1 ml of methanol and then with 1 ml of1% NH₃ in water. Samples were then diluted with 700 μl of 1% NH₃ inwater and loaded. The plate was washed with 1 ml of methanol/1% NH₃ inwater 5/95. Elution was performed using 1 ml of 0.1% TFA in methanol.

The plate containing eluates was introduced into the concentrator systemand taken to dryness. The residues were dissolved in 100 μL of formicacid 0.1%/acetonitrile, 95/5 (v/v) and analysed in the HPLC/MS on areverse phase analytical column (Jupiter C 18, 50×2.0 mm, 5 μm,Phenomenex), using gradient elution (mobile phases A: 0.1% formic acidin water, B: Acetonitrile; from 5% B to 100% B in 2 min.).

Preparation of Plasma Samples

Samples coming from animal treatments were pooled in order to obtain anappropriate volume for the extraction. If the total volume obtained wasless than 0.2 ml the appropriate amount of “blank” mouse plasma wasadded in order to keep the matrix identical to the calibration curve.Samples were than spiked with IS and processed as described for thecalibration curve.

Pharmacokinetic Evaluation

PK analysis was performed on pooled data (generally n=2 or 3) using thesoftware Win Nonlin (Pharsight). The area under the curve AUC wascalculated by the linear trapezoidal rule. Elimination half-life wascalculated by the linear regression on at least three data points duringthe elimination phase. The time intervals selected for the half-lifedeterminations were evaluated by the correlation coefficient (r²), whichshould be at least above 0.85 and most optimally above 0.96. In case ofi.v. administration the initial concentration at t_(zero) was determinedby extrapolation of the curve through the first two time points. Finallybioavailability after i.p. administration was calculated from thenormalised AUCinf_D_obs ration after s.c. versus i.v. administration.

2.7. In Vivo Septicemia Assay

Groups of 6 CD-1 (Crl.) derived male mice weighing 24±2 g were used. Themice were each inoculated intravenously (IV) with an LD90-100 ofPseudomonas aeruginosa (ATCC 27853)(9×106 CFU/0.5 ml/mouse) in brainheart infusion broth without 5% mucin. Compound at doses of 5, 2.5, 1,0.5, 0.25 and 0.1 mg/kg, vehicle (0.9% NaCl, 10 ml/kg) was administeredsubcutaneously (SC) to test animals at 1 hour after bacterialinoculation. Also, an additional group was treated twice with compoundat a dose of 5 mg/kg at 1 and 6 hours after bacterial inoculation.Mortality was recorded once daily for 7 days following the bacterialinoculation and an increase of survival of the animals by 50 percent ormore (³50%) after the bacterial inoculation, relative to vehiclecontrol, indicates significant antimicrobial effect. The MED (ED50) wasdetermined by nonlinear regression using Graph-Pad Prism (Graph PadSoftware, USA).

2.8. Results

The results of the experiments described in 2.2, 2.3 and 2.4, above, areindicated in Table 2, herein below

TABLE 2 Minimal inhibitory concentrations (MIC in μg/ml) inMueller-Hinton broth, cytotoxicity and percentage hemolyses at aconcentration of 100 μg/ml of peptide P. aeruginosa P. aeruginosa P.aeruginosa P. aeruginosa P. aeruginosa Average Cytotoxicity HemolysisEx. ATCC 27853 P8191900 P1021903 P1021913 IMP1 Livermore 3140 MIC GI₅₀Hela Cells at 100 μg/ml 1 0.03 0.07 0.07 0.13 0.18 0.10 30 0.5 2 0.040.10 0.16 0.18 0.24 0.15 50 0.3 3 0.09 0.30 0.30 0.31 2.0 0.6 34 0.6 40.75 1.50 1.50 2.50 >2.0 >1 40 0.6 5 0.08 0.30 0.21 0.21 0.75 0.31 500.6 6 0.05 0.10 0.09 0.16 0.24 0.13 50 0.2 7 0.13 0.50 1.50 0.65 >2 >113 0.8 8 0.05 0.18 0.18 0.31 0.43 0.23 50 0 9 0.21 0.75 1.50 0.75 >2 >150 0.7 10 0.05 0.18 0.13 0.37 0.43 0.23 50 0 11 0.30 1.00 2.000.75 >2 >1 50 0.5 12 0.40 1.00 2.00 0.75 >2 >1 50 0.7 13 0.21 0.30 0.400.31 0.75 0.40 50 0.4 14 0.21 0.40 0.31 0.65 >2 >1 12 0.3 15 0.50 2.501.25 2.25 >2 >1 50 0.3 16 0.05 0.09 0.05 0.10 0.24 0.11 50 0.1 17 0.751.50 2.00 1.25 >2 >1 29 0.5 18 0.06 0.10 0.10 0.81 0.30 0.28 50 0.4 190.03 0.05 0.03 0.10 0.10 0.06 50 0.2 20 0.21 0.40 0.21 0.31 1.25 0.48 500.2 21 0.09 0.40 0.21 0.31 1.00 0.40 50 0.4 22 0.02 0.09 0.09 0.16 0.240.12 50 0.2 23 1.00 1.00 1.50 1.25 >2 >1 13 0.5 24 0.05 0.16 0.08 0.160.24 0.14 50 0.1 25 0.05 0.10 0.05 0.13 0.24 0.11 50 0.1 26 0.08 0.300.13 0.18 0.40 0.22 50 0.8 27 0.09 0.30 0.30 0.21 0.50 0.28 50 0.6 280.04 0.10 0.07 0.16 0.24 0.12 50 0.1 29 0.09 0.13 0.13 0.21 0.40 0.19 500.5 30 0.09 0.13 0.30 0.50 2.00 0.60 46 0.5 31 0.03 0.16 0.40 0.16 0.240.20 50 0.5 32 0.02 0.05 0.05 0.10 0.22 0.09 50 0 33 0.05 0.18 0.29 0.310.43 0.25 50 0.1 34 0.05 0.24 0.29 0.48 0.60 0.33 50 0 35 0.05 0.22 0.100.24 0.31 0.18 48 0.2 36 0.06 0.18 0.18 0.24 0.43 0.22 50 0.1 37 0.060.18 0.31 0.37 1.17 0.42 50 0.5 38 0.09 0.17 0.17 0.27 1.06 0.35 50 0.539 0.13 0.21 0.31 0.31 0.75 0.34 50 0.4 40 0.25 0.50 0.50 0.50 1.00 0.5550 0.7 41 0.02 0.05 0.03 0.25 0.25 0.12 50 0.2 42 0.25 0.06 0.125 0.500.50 0.29 50 0.2 43 0.13 0.50 0.125 2.00 2.00 0.95 50 0.5 45 0.25 0.500.50 1.00 1.00 0.65 50 0.2 46 0.06 0.25 0.25 0.50 0.50 0.31 50 0.3 470.09 0.13 0.13 0.50 0.75 0.32 50 0.2 48 0.02 0.03 0.02 0.13 0.19 0.08 500.2 49 0.03 0.06 0.03 0.25 0.50 0.17 50 0.1 50 0.09 0.13 0.06 0.50 2.000.56 50 n.d. n.d. = not determined

The results of the experiment described in 2.5, above, are indicated inTable 3 herein below.

TABLE 3 Stability human Stability rat Ex. Plasma t_(1/2) (min) Plasmat_(1/2) (min) 1 300 300 2 300 300 6 300 300 16 300 300 22 300 300 24 300300 25 300 300 28 300 300 29 300 300 32 300 300 35 300 300

The results of the experiment described in 2.6 (PK), above, areindicated in Table 4 herein below.

TABLE 4 Administration route Parameters Dimensions I.V. S.C. HL_Lambda_zhr 0.53 0.95 Tmax hr 0.08 0.58 Cmax ng/mL 1268.0 2333.3 Cmax_Dkg*ng/mL/mg 1268.0 466.7 C0 ng/mL 2174.0 — AUCINF_obs hr*ng/mL 679.54016.5 AUCINF_D_obs hr*kg*ng/mL/mg 679.5 803.3 Vz_obs mL/kg 1136.11705.6 Cl_obs mL/hr/kg 1539.1 1249.8 Bioavailability % 100 118.2

After intravenous administration of Ex. 1 at a dose level of 1 mg/kgbody weight, Ex. 1 followed intravenous kinetic characteristics. AfterPK analysis, Ex. 1 showed an extrapolated C_(initial) of 2174 ng/ml anda C_(max) observed of 1268 ng/ml at 5 min. Plasma levels rapidlydecreased to 575 and 177 ng/ml at 15 min and 1 hour respectively. From0.5 to 2 h plasma levels decreased with an elimination half-life of 0.53h to 10.6 ng/ml at 3 h. The AUCINF_obs amounted to 679.5 ng·h/ml.

After subcutaneous administration of Ex. 1 at a dose level of 5 mg/kgbody weight, plasma levels of Ex. 1 increased the first 0.5-1 h andshowed a C_(max) of 2333 ng/ml. From 0.5 to 8 h plasma levels decreasedwith an elimination half-life of 0.95 h to 7.3 ng/ml at 8 h. TheAUCINF_obs amounted to 4016.5 ng·h/ml.

As compared to the normalized AUC value after i.v. administration (100%absorbed, 679 ng·h/ml) of Ex. 1 absorbed after s.c. administrationamounted to 118% (803 ng·h/ml). The value above 100% may partiallyreflect an impaired reliability caused by the limited number of pointsor is caused by a non-linearity in dose.

The results of the experiment described in 2.7 (Septicaemia Assay),above, are indicated in Table 5-7 herein below.

Septicaemia experiment in mice: LD90-100 of Pseudomonas aeruginosa (ATCC27853) (9×106 CFU/0.5 ml/mouse IV and after 1 h Ex. 1 s.c.

TABLE 5 Compound/dose Dead Survivors Negative control 5 1 Gentamycin, 1mg/kg 0 6 Compound of Example 1 in following doses (mg/kg) 10 (2 × 5) 06 5 0 6 2.5 0 6 1 1 5 0.5 2 4 0.25 5 1 0.1 5 1

Septicaemia experiment in mice: LD90-100 of Pseudomonas aeruginosa (ATCC27853) (9×106 CFU/0.5 ml/mouse N), and after 1 and 5 h Ex. 40 s.c.

TABLE 6 Compound/dose Dead Survivors Negative control 6 0 Gentamycin, 2× 1 mg/kg 1 5 Compound of Example 40 in following doses (mg/kg) 2 × 10 0 6 2 × 3   0 6 2 × 1   2 4 2 × 0.3 6 0 2 × 0.1 6 0

Septicaemia experiment in mice: LD90-100 of Pseudomonas aeruginosa (ATCC27853) (9×106 CFU/0.5 ml/mouse IV), and after 1 and 5 h Ex. 50 s.c.

TABLE 7 Compound/dose Dead Survivors Negative control 5 1 Gentamycin, 2× 1 mg/kg 1 5 Compound of Example 50 in following doses (mg/kg) 2 × 10 0 6 2 × 3   3 3 2 × 1   5 1 2 × 0.3 6 0 2 × 0.1 6 0

REFERENCES

-   1. National Committee for Clinical Laboratory Standards. 1993.    Methods for dilution antimicrobial susceptibility tests for bacteria    that grow aerobically, 3rd ed. Approved standard M7-A3. National    Committee for Clinical laboratory standards, Villanova, Pa.-   2. Mossman T. J Immunol Meth 1983, 65, 55-63-   3. Berridge M V, Tan A S. Archives of Biochemistry & Biophysics    1993, 303, 474-482

1-46. (canceled)
 47. A method of making a pharmaceutical composition,comprising combining a pharmaceutically inert carrier and a compoundrepresented by formula (I):

wherein

is ^(D)Pro-^(L)Pro and Z is a chain of 12 α-amino acid residues, whereinthe positions of the amino acid residues in the chain are countedstarting from the N-terminal amino acid, wherein the amino acid residuesare, in positions P1 to P12 of the chain: P1: Thr; P2: Trp; P3: Ile; P4:Dab; P5: Orn; P6: ^(D)Dab; P7: Dab; P8: Trp; P9 Dab; P10: Dab; P11: Ala;and P12: Ser, or a pharmaceutically acceptable salt or enantiomerthereof.
 48. A method of treating a disease or infection comprisingadministering to a subject in need thereof an effective amount of acompound represented by formula (I):

wherein

is ^(D)Pro-^(L)Pro and Z is a chain of 12 α-amino acid residues, whereinthe positions of the amino acid residues in the chain are countedstarting from the N-terminal amino acid, wherein the amino acid residuesare, in positions P1 to P12 of the chain: P1: Thr; P2: Trp; P3: Ile; P4:Dab; P5: Orn; P6: ^(D)Dab; P7: Dab; P8: Trp; P9 Dab; P10: Dab; P11: Ala;and P12: Ser, or a pharmaceutically acceptable salt or enantiomerthereof.
 49. The method of claim 48, wherein said infection is relatedto respiratory diseases such as cystic fibrosis, emphysema and asthma;related to skin or soft tissue diseases such as surgical wounds,traumatic wounds or burn wounds; related to gastrointestinal diseasessuch as epidemic diarrhea, necrotizing enterocolitis or typhlitis;related to eye diseases such as keratitis or endophthalmitis; related toear diseases such as otitis; related to CNS diseases such as brainabscess or meningitis; related to bone diseases such as osteochondritisor osteomyelitis; related to cardiovascular diseases such asendocartitis or pericarditis; related to gastrourinal diseases such asepididymitis, prostatitis or urethritis; related to cancer; or relatedto HIV.
 50. A method of disinfecting or preserving a foodstuff,cosmetic, medicament and or nutrient-containing material, comprisingadding to a foodstuff, cosmetic, medicament and or nutrient-containingmaterial an effective amount of a compound represented by formula (I):

wherein

is ^(D)Pro-^(L)Pro and Z is a chain of 12 α-amino acid residues, whereinthe positions of the amino acid residues in the chain are countedstarting from the N-terminal amino acid, wherein the amino acid residuesare, in positions P1 to P12 of the chain: P1: Thr; P2: Trp; P3: Ile; P4:Dab; P5: Orn; P6: ^(D)Dab; P7: Dab; P8: Trp; P9 Dab; P10: Dab; P11: Ala;and P12: Ser, or a pharmaceutically acceptable salt or enantiomerthereof.
 51. A process for producing a compound represented by formula(I):

wherein

is ^(D)Pro-^(L)Pro and Z is a chain of 12 α-amino acid residues, whereinthe positions of the amino acid residues in the chain are countedstarting from the N-terminal amino acid, wherein the amino acid residuesare, in positions P1 to P12 of the chain: P1: Thr; P2: Trp; P3: Ile; P4:Dab; P5: Orn; P6: ^(D)Dab; P7: Dab; P8: Trp; P9 Dab; P10: Dab; P11: Ala;and P12: Ser, or a pharmaceutically acceptable salt or enantiomerthereof, comprising: (a) coupling an appropriately functionalized solidsupport with an appropriately N-protected derivative of that amino acidwhich in the desired end-product is in position 5, 6 or 7, anyfunctional group which may be present in said N-protected amino acidderivative being likewise appropriately protected; (b) removing theN-protecting group from the product thus obtained; (c) coupling theproduct thus obtained with an appropriately N-protected derivative ofthat amino acid which in the desired end-product is one position nearerthe N-terminal amino acid residue, any functional group which may bepresent in said N-protected amino acid derivative being likewiseappropriately protected; (d) removing the N-protecting group from theproduct thus obtained; (e) repeating steps (c) and (d) until theN-terminal amino acid residue has been introduced; (f) coupling theproduct thus obtained with a compound of the general formula

wherein

is as defined above and X is an N-protecting group; (g) removing theN-protecting group from the product obtained in step (f); (h) couplingthe product thus obtained with an appropriately N-protected derivativeof that amino acid which in the desired end-product is in position 12,any functional group which may be present in said N-protected amino acidderivative being likewise appropriately protected; (i) removing theN-protecting group from the product thus obtained; (j) coupling theproduct thus obtained with an appropriately N-protected derivative ofthat amino acid which in the desired end-product is one position fartheraway from position 12, any functional group which may be present in saidN-protected amino acid derivative being likewise appropriatelyprotected; (k) removing the N-protecting group from the product thusobtained; (l) repeating steps (j) and (k) until all amino acid residueshave been introduced; (m) if desired, selectively deprotecting one orseveral protected functional group(s) present in the molecule andappropriately substituting the reactive group(s) thus liberated; (o)detaching the product thus obtained from the solid support; (p)cyclizing the product cleaved from the solid support; (q) optionally,forming one or two interstrand linkage(s) between side-chains ofappropriate amino acid residues at opposite positions of the β-strandregion; (r) removing any protecting groups present on functional groupsof any members of the chain of amino acid residues and, optionally, anyprotecting group(s) which may in addition be present in the molecule;and (s) optionally, converting the product thus obtained into apharmaceutically acceptable salt or converting a pharmaceuticallyacceptable, or unacceptable, salt thus obtained into the correspondingfree compound of formula I or into a different, pharmaceuticallyacceptable, salt.
 52. The process of claim 51, wherein enantiomers ofall chiral starting materials are used.
 53. A process for themanufacture of a compound represented by formula (I):

wherein

is ^(D)Pro-^(L)Pro and Z is a chain of 12 α-amino acid residues, whereinthe positions of the amino acid residues in the chain are countedstarting from the N-terminal amino acid, wherein the amino acid residuesare, in positions P1 to P12 of the chain: P1: Thr; P2: Trp; P3: Ile; P4:Dab; P5: Orn; P6: ^(D)Dab; P7: Dab; P8: Trp; P9 Dab; P10: Dab; P11: Ala;and P12: Ser, or a pharmaceutically acceptable salt or enantiomerthereof, comprising: (a′) coupling an appropriately functionalized solidsupport with a compound of the general formula

wherein

is as defined above and X is an N-protecting group; (b′) removing theN-protecting group from the product obtained in step (a′); (c′) couplingthe product thus obtained with an appropriately N-protected derivativeof that amino acid which in the desired end-product is in position 12,any functional group which may be present in said N-protected amino acidderivative being likewise appropriately protected; (d′) removing theN-protecting group from the product thus obtained; (e′) coupling theproduct thus obtained with an appropriately N-protected derivative ofthat amino acid which in the desired end-product is one position fartheraway from position 12, any functional group which may be present in saidN-protected amino acid derivative being likewise appropriatelyprotected; (f′) removing the N-protecting group from the product thusobtained; (g′) repeating steps (e′) and (f′) until all amino acidresidues have been introduced; (h′) optionally, selectively deprotectingone or several protected functional group(s) present in the molecule andappropriately substituting the reactive group(s) thus liberated; (i′)detaching the product thus obtained from the solid support; (j′)cyclizing the product cleaved from the solid support; (k′) optionally,forming one or two interstrand linkage(s) between side-chains ofappropriate amino acid residues at opposite positions of the β-strandregion; (l′) removing any protecting groups present on functional groupsof any members of the chain of amino acid residues and, if desired, anyprotecting group(s) which may in addition be present in the molecule;and (m′) optionally, converting the product thus obtained into apharmaceutically acceptable salt or converting a pharmaceuticallyacceptable, or unacceptable, salt thus obtained into the correspondingfree compound of formula I or into a different, pharmaceuticallyacceptable, salt.
 54. The process of claim 53, wherein enantiomers ofall chiral starting materials are used.
 55. A method of making apharmaceutical composition, comprising combining a pharmaceuticallyinert carrier and a compound represented by formula (I):

wherein

is ^(L)Pro-^(D)Pro and Z is a chain of 12 α-amino acid residues, whereinthe positions of the amino acid residues in the chain are countedstarting from the N-terminal amino acid, wherein the amino acid residuesare, in positions P1 to P12 of the chain: P1: Thr; P2: Trp; P3: Ile; P4:Dab; P5: Orn; P6: ^(D)Dab; P7: Dab; P8: Trp; P9 Dab; P10: Dab; P11: Ala;and P12: Ser, or a pharmaceutically acceptable salt or enantiomerthereof.
 56. A method of treating a disease or infection comprisingadministering to a subject in need thereof an effective amount of acompound represented by formula (I):

wherein

is ^(L)Pro-^(D)Pro and Z is a chain of 12 α-amino acid residues, whereinthe positions of the amino acid residues in the chain are countedstarting from the N-terminal amino acid, wherein the amino acid residuesare, in positions P1 to P12 of the chain: P1: Thr; P2: Trp; P3: Ile; P4:Dab; P5: Orn; P6: ^(D)Dab; P7: Dab; P8: Trp; P9 Dab; P10: Dab; P11: Ala;and P12: Ser, or a pharmaceutically acceptable salt or enantiomerthereof.
 57. The method of claim 56, wherein said infection is relatedto respiratory diseases such as cystic fibrosis, emphysema and asthma;related to skin or soft tissue diseases such as surgical wounds,traumatic wounds or burn wounds; related to gastrointestinal diseasessuch as epidemic diarrhea, necrotizing enterocolitis or typhlitis;related to eye diseases such as keratitis or endophthalmitis; related toear diseases such as otitis; related to CNS diseases such as brainabscess or meningitis; related to bone diseases such as osteochondritisor osteomyelitis; related to cardiovascular diseases such asendocartitis or pericarditis; related to gastrourinal diseases such asepididymitis, prostatitis or urethritis; related to cancer; or relatedto HIV.
 58. A method of disinfecting or preserving a foodstuff,cosmetic, medicament and or nutrient-containing material, comprisingadding to a foodstuff, cosmetic, medicament and or nutrient-containingmaterial an effective amount of a compound represented by formula (I):

wherein

is ^(L)Pro-^(D)Pro and Z is a chain of 12 α-amino acid residues, whereinthe positions of the amino acid residues in the chain are countedstarting from the N-terminal amino acid, wherein the amino acid residuesare, in positions P1 to P12 of the chain: P1: Thr; P2: Trp; P3: Ile; P4:Dab; P5: Orn; P6: ^(D)Dab; P7: Dab; P8: Trp; P9 Dab; P10: Dab; P11: Ala;and P12: Ser, or a pharmaceutically acceptable salt or enantiomerthereof.
 59. A process for producing a compound represented by formula(I):

wherein

is ^(L)Pro-^(D)Pro and Z is a chain of 12 α-amino acid residues, whereinthe positions of the amino acid residues in the chain are countedstarting from the N-terminal amino acid, wherein the amino acid residuesare, in positions P1 to P12 of the chain: P1: Thr; P2: Trp; P3: Ile; P4:Dab; P5: Orn; P6: ^(D)Dab; P7: Dab; P8: Trp; P9 Dab; P10: Dab; P11: Ala;and P12: Ser, or a pharmaceutically acceptable salt or enantiomerthereof, comprising: (a) coupling an appropriately functionalized solidsupport with an appropriately N-protected derivative of that amino acidwhich in the desired end-product is in position 5, 6 or 7, anyfunctional group which may be present in said N-protected amino acidderivative being likewise appropriately protected; (b) removing theN-protecting group from the product thus obtained; (c) coupling theproduct thus obtained with an appropriately N-protected derivative ofthat amino acid which in the desired end-product is one position nearerthe N-terminal amino acid residue, any functional group which may bepresent in said N-protected amino acid derivative being likewiseappropriately protected; (d) removing the N-protecting group from theproduct thus obtained; (e) repeating steps (c) and (d) until theN-terminal amino acid residue has been introduced; (f) coupling theproduct thus obtained with a compound of the general formula

wherein

is as defined above and X is an N-protecting group; (g) removing theN-protecting group from the product obtained in step (f); (h) couplingthe product thus obtained with an appropriately N-protected derivativeof that amino acid which in the desired end-product is in position 12,any functional group which may be present in said N-protected amino acidderivative being likewise appropriately protected; (i) removing theN-protecting group from the product thus obtained; (j) coupling theproduct thus obtained with an appropriately N-protected derivative ofthat amino acid which in the desired end-product is one position fartheraway from position 12, any functional group which may be present in saidN-protected amino acid derivative being likewise appropriatelyprotected; (k) removing the N-protecting group from the product thusobtained; (l) repeating steps (j) and (k) until all amino acid residueshave been introduced; (m) if desired, selectively deprotecting one orseveral protected functional group(s) present in the molecule andappropriately substituting the reactive group(s) thus liberated; (o)detaching the product thus obtained from the solid support; (p)cyclizing the product cleaved from the solid support; (q) optionally,forming one or two interstrand linkage(s) between side-chains ofappropriate amino acid residues at opposite positions of the β-strandregion; (r) removing any protecting groups present on functional groupsof any members of the chain of amino acid residues and, optionally, anyprotecting group(s) which may in addition be present in the molecule;and (s) optionally, converting the product thus obtained into apharmaceutically acceptable salt or converting a pharmaceuticallyacceptable, or unacceptable, salt thus obtained into the correspondingfree compound of formula I or into a different, pharmaceuticallyacceptable, salt.
 60. The process of claim 59, wherein enantiomers ofall chiral starting materials are used.
 61. A process for themanufacture of a compound represented by formula (I):

wherein

is ^(L)Pro-^(D)Pro and Z is a chain of 12 α-amino acid residues, whereinthe positions of the amino acid residues in the chain are countedstarting from the N-terminal amino acid, wherein the amino acid residuesare, in positions P1 to P12 of the chain: P1: Thr; P2: Trp; P3: Ile; P4:Dab; P5: Orn; P6: ^(D)Dab; P7: Dab; P8: Trp; P9 Dab; P10: Dab; P11: Ala;and P12: Ser, or a pharmaceutically acceptable salt or enantiomerthereof, comprising: (a′) coupling an appropriately functionalized solidsupport with a compound of the general formula

wherein

is as defined above and X is an N-protecting group; (b′) removing theN-protecting group from the product obtained in step (a′); (c′) couplingthe product thus obtained with an appropriately N-protected derivativeof that amino acid which in the desired end-product is in position 12,any functional group which may be present in said N-protected amino acidderivative being likewise appropriately protected; (d′) removing theN-protecting group from the product thus obtained; (e′) coupling theproduct thus obtained with an appropriately N-protected derivative ofthat amino acid which in the desired end-product is one position fartheraway from position 12, any functional group which may be present in saidN-protected amino acid derivative being likewise appropriatelyprotected; (f′) removing the N-protecting group from the product thusobtained; (g′) repeating steps (e′) and (f′) until all amino acidresidues have been introduced; (h′) optionally, selectively deprotectingone or several protected functional group(s) present in the molecule andappropriately substituting the reactive group(s) thus liberated; (i′)detaching the product thus obtained from the solid support; (j′)cyclizing the product cleaved from the solid support; (k′) optionally,forming one or two interstrand linkage(s) between side-chains ofappropriate amino acid residues at opposite positions of the β-strandregion; (l′) removing any protecting groups present on functional groupsof any members of the chain of amino acid residues and, if desired, anyprotecting group(s) which may in addition be present in the molecule;and (m′) optionally, converting the product thus obtained into apharmaceutically acceptable salt or converting a pharmaceuticallyacceptable, or unacceptable, salt thus obtained into the correspondingfree compound of formula I or into a different, pharmaceuticallyacceptable, salt.
 62. The process of claim 61, wherein enantiomers ofall chiral starting materials are used.